Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus

ABSTRACT

Methods for treating gestational diabetes which comprise administration of an effective amount of an exendin or an exendin agonist, alone or in conjunction with other compounds or compositions that lower blood glucose levels.

FIELD OF THE INVENTION

[0001] The present invention relates to methods for treating gestationaldiabetes mellitus comprising administration of an effective amount of anexendin or an exendin agonist alone or in conjunction with othercompounds or compositions that affect blood glucose control, such as aninsulin or an amylin agonist. Pharmaceutical compositions for use in themethods of the invention are also disclosed.

BACKGROUND

[0002] The following description summarizes information relevant to thepresent invention. It is not an admission that any of the informationprovided herein is prior art to the presently claimed invention, northat any of the publications specifically or implicitly referenced areprior art to that invention.

[0003] Gestational Diabetes Mellitus Gestational diabetes mellitus(“GDM”) is a disorder associated with elevated circulating plasmaglucose. Although the diagnostic criteria for GDM have been the subjectof controversy for decades, it was defined by the Third WorkshopConference on Gestational Diabetes Mellitus as carbohydrate intoleranceof varying severity with onset or first recognition during pregnancy,irrespective of the glycemic status after delivery. Metzger (ed.)Proceedings of the Third International Workshop Conference onGestational Diabetes Mellitus, Diabetes 40(Suppl. 2), 1991. Despiteadvances in clinical management of GDM, there are problems associatedwith GDM which persist, including elevated rate of perinatal morbidityand elevated rate of malformations in newborns. Persson et al., Diabetesand Pregnancy, In International Textbook of Diabetes Mellitus, SecondEdition, John Wiley & Sons 1997 (Alberti et al. Eds.). For example, ithas been reported that, when the mean blood glucose level is greaterthan 105 mg/dl, there is a greater risk for the P development oflarge-for-gestational age (“LGA”) infants when compared with a controlpopulation. Id. Additional reported consequences of untreated GDMinclude an increased incidence of macrosomia, respiratory distresssyndrome, and other abnormalities of fetal metabolism. Langer, Am. J.Obstet Gynecol. 176:S186, 1997; American Diabetes Association:Self-Monitoring of Blood-Glucose Consensus Statement, Diabetes Care17:81-82, 1994(“ABA Consensus Statement”); Coetzee & Jackson, S. Afr.Med. J. 56:467-475, 1979. It has been clearly established by those inthe field that tight glycemic control can serve as the primaryprevention of fetal disease relating to GDM. Drexel et al., DiabetesCare 11:761-768, 1988; Roversi et al., Diabetes Care 3:489-494,.1980;Langer & Mazze, Am. J. Obstet Gynecol. 159:1478-1483, 1988; Langer etal., Am. J. Obstet Gynecol. 161:646-653, 1989). GDM results in a greaterincidence of intrauterine death or neonatal mortality. PositionStatement American Diabetes Association: Gestational Diabetes Mellitus,Diabetes Care 21 (Suppl. 1):S60-61, 1998. GDM pregnancies are at anincreased risk for fetal macrosomia and neonatal morbidities includingneural tube defects, hypoglycemia, hypocalcemiea, hypomagnsemia,polycythemia and hyperbilirubinemia and subsequent childhood andadolescent obesity. Siccardi, Gestational Diabetes. Other complicationsto the woman include increased rates of cesarean delivery, hypertensivedisorders including preeclamsia and urinary tract infections.

[0004] It has been reported that approximately 4% of all pregnancies(135,000 cases annually) are complicated by GDM, however, it has beenestimated that the incidence may range from 1% to 14% of allpregnancies, depending on the population and diagnostic tests employed.ADA Consensus Statement, supra.

[0005] Normally during pregnancy, fasting plasma levels of insulingradually increase to reach concentrations that are approximately twiceas high in the third trimester as they were outside of pregnancy. Womenwith gestational diabetes mellitus (“GDM”) have fasting insulin levelscomparable to or higher than those of normal pregnant women with thehighest levels seen in women with GDM who are obese. Insulin secretionalso increases gradually in pregnancy and also reaches a maximum duringthe third trimester. However, the relative increase in secretion issignificantly smaller in women with GDM than in normal glucose tolerant(“NGT”) women. The first-phase insulin response in NGT women issignificantly higher than in GDM women; second phase insulin responsewas similarly increased during pregnancy in both groups. This finding isconsistent with the finding that GDM women have a later time of peakinsulin concentration during an oral glucose tolerance test than do NGTwomen. Consistent with this observation, the insulin response per unitof glycemic stimulus is significantly higher in NGT women than in GDMwomen (90% and 40%, respectively). The fact that glucose tolerancedeteriorates in both normal and GDM pregnancies while at the same time,insulin secretion increases indicates a decrease in insulin sensitivity.Comparative results from an intravenous glucose tolerance test and ahyperinsulinemic, euglycemic clamp showed a sensitivity decrease duringpregnancy in both groups of 50-60%, but GDM women had a slightly lowersensitivity. In another study using radioactive glucose, turnover ofglucose and amino acids in GDM women was comparable to NGT women onlywhen insulin concentrations 3-5 fold higher in the GDM group were used.Thus, it appears that GDM is due to a combination of diminished insulinsensitivity and an impaired ability to increase insulin secretion andhas, in fact, many features in common with type 2 diabetes. Normal ornear normal glycemic control returns upon parturition.

[0006] Clinical Diagnosis:

[0007] It is common clinical practice to screen women for elevatedglucose and glucose intolerance between weeks 24 and 28 of gestation,especially women with any one the following four characteristics: age≧25; race/ethnicity of Hispanic, Native American, Asian,African-American or Pacific Islander origin; obese or a family historyof diabetes. In addition, women with previous pregnancies withcomplications due to a large weight fetus/neonate are usually tested. Insome medical centers all pregnant-women are tested. Indeed, certaininvestigators have found that historical risk factors account for onlyroughly half of the women known to have GDM. Carr, Diabetes Care21(Suppl. 2):B14-B18, 1998. Additionally, there is some reportedevidence that advancing maternal age is associated with increasedincidence of GDM. Id.

[0008] The clinical diagnosis is generally based on a multi-stepprocess. The evaluation is most typically performed by measuring plasmaglucose 1 hour after a 50-gram oral glucose challenge test in either thefasted or the unfasted state. If the value in the glucose challenge testis ≧140 mg/dl, a 3-hr 100 g oral glucose tolerance test is done. If twoor more of the following criteria are met, the patient is considered inneed of glycemic control: fasted venous plasma ≧105 mg/dl, venous plasma≧190 mg/dl. at 1 hr, venous plasma ≧165 mg/dl at 2 hr or venous plasma≧145 mg/dl at 3 hr. Williams et al., Diabetes Care 22: 418-421, 1999.Variations of this test are also used by some. See, e.g., Coustan,Gestational Diabetes In Diabetes in America, 2d ed. National Institutesof Health Publication No. 95-1468, 1995.

[0009] Current Clinical Therapy:

[0010] The current therapeutic approach for GDM is to control plasmaglucose for the remainder of the gestation (i.e., the third trimesterthrough parturition). GDM has many features in common with type 2diabetes. The endocrine (impaired insulin secretion) and metabolic(insulin resistance) abnormalities that characterize both forms ofdiabetes are similar. In general, pregnancy is characterized byincreases in both insulin resistance and insulin secretion. Women withGDM fail to respond with increased insulin to the decrease in insulinsensitivity.

[0011] A significant correlation has been shown to exist betweenlate-stage gestational maternal glucose levels and preeclamsia,macrosomia, Cesarean section delivery and phototherapy forhyperbilirubinemia. Sermer et al., Diabetic Care 21 (Suppl. 2):B33-B42,1998. It has also been determined that the length of hospitalization ofthe new mother and the length of time the neonate spent in the nurserycould be correlated to the degree of elevation of plasma glucose in thepregnant woman. Id. Tallarigo, et al. reported a striking rise in therisk of fetal macrosomia (9.9 vs. 27.5%) and preeclamsia/Cesareansections (19.9 vs. 40.0%) in women with abnormal glucose tolerance whencompared to NGT women. Tallarigo et al., N. Engl. J. Med. 315:989-992,1986.

[0012] Thus, the goals for therapy of GDM are to achieve and maintain asnear normal glycemia as feasible with a special emphasis to keeppostprandial glucose concentrations within the normal range. Optimaltherapeutic strategies are safe and efficacious in achieving a metabolicbalancing without creating complications, which may include ketosisand/or hypoglycemia. Jovanovic, Diabetes Care 21(Suppl. 2):B131-B137,1998. The initial therapeutic approach is through. diet.Jovanovic-Peterson & Peterson, J. Am. Coll. Nutr. 9:320-325, 1990.

[0013] If diet or diet and exercise are not effective (i.e., failure isfasting glucose ≧105 mg/dl and/or a 2-hr postprandial plasma glucose of≧120 mg/dl on 2 or more occasions within a 1- to 2-week period), theninsulin therapy (preferably, human insulin) is considered appropriate.ADA Position Statement, supra.

[0014] Oral glucose-lowering agents are not recommended duringpregnancy. Kuhl et al., Diabetic Care 21 (Suppl. 2): B19-B26, 1998.Although sulfonylureas are used in the treatment of type 2 diabetes dueto their activity in increasing insulin sensitivity these agents arecontraindicated for use in GDM. Jovanovlic, Diabetes Care 21 (Suppl.2):B131-B137, 1998. See also Kahn & Shechter, Insulin, Oral HypoglycemicAgents, and the Pharmacology of the Endocrine Pancreas, In Goodman &Gilman's The Pharmacological Basis of Therapeutics (8^(th) ed. 1993Goodman Gilman et al. eds.). Oral hypoglycemic drugs traverse theplacenta, and may cause prolonged severe hypoglycemia in the newborn.Persson et al., supra.

[0015] The difficulties with, and the highly variable approaches toinsulin therapy in GDM have been reviewed, for example, by Langer, etal. Langer, Diabetes Care 21(Suppl.2):B91-B98, 1998. The problemscommonly associated, with insulin therapy in a non-pregnant populationremain when used in the treatment of GDM. They are determination of theproper dose, maintenance of good glucose control through each 24-hrperiod, possible hypoglycemia and weight gain. Hypoglycemia can resultwhen insulin is administered to control postprandial plasma glucose, butthe fetus demands for energy in the presence of excess insulin latercauses the glucose level to drop to a hypoglycemic level. Thisphysiological state can be dangerous to both the mother and the fetus.Excess weight gain is undesirable in any pregnancy. Another problem withinsulin therapy is the day-to-day and week-to-week variability inglucose control vs. insulin dose.

[0016] Thus, it can be appreciated that an effective means to treatgestational diabetes remains a major challenge and a superior method oftreatment would be of great utility. Such a method, and compounds andcompositions which are useful therefor, have been invented and aredescribed and claimed herein.

[0017] Exendins and Exendin Agonists

[0018] Exendins are peptides that were first isolated form the salivarysecretions of the Gila-monster, a lizard found in Arizona, and theMexican Beaded Lizard. Exendin-3 is present in the salivary secretionsof Heloderma horridum, and exendin-4 is present in the salivarysecretions of Heloderma suspectum (Eng, J., et al., J. Biol. Chem.,265:20259-62, 1990; Eng., J., et al., J. Biol. Chem., 267:7402-05,1992). The exendins have some sequence similarity to several members ofthe glucagon-like peptide family, with the highest homology, 53%, beingto GLP-1[7-36]NH₂ (Goke, et al., J. Biol. Chem., 268:19650-55,. 1993).GLP-1[7-36]NH₂, also known as proglucagon[78-107] and most commonly as“GLP-1,” has an insulinotropic effect, stimulating insulin secretionfrom pancreatic β-cells; GLP-1 also inhibits glucagon secretion frompancreatic α-cells (Orskov, et al., Diabetes, 42:658-61, 1993;D'Alessio, et al., J. Clin. Invest., 97:133-38, 1996). GLP-1 is reportedto inhibit gastric emptying (Williams B. et al., J Clin Endocrinol Metab81 (1): 327-32, 1996; Wettergren A, et al., Dig Dis Sci 38 (4): 665-73,1993), and gastric acid secretion. (Schjoldager B T, et al., Dig Dis Sci34 (5): 703-8, 1989; O'Halloran D J, et al., J Endocrinol 126 (1):169-73, 1990; Wettergren A, et al., Dig Dis Sci 38 (4): 665-73, 1993).GLP-1[7-37], which has an additional glycine residue at its carboxyterminus, also stimulates insulin secretion in humans (Orskov, et al.,Diabetes, 42:658-61, 1993). A transmembrane G-proteinadenylate-cyclase-coupled receptor believed to be responsible for theinsulinotropic effect of GLP-1 is reported to have been cloned from aβ-cell line (Thorens, Proc. Natl. Acad. Sci. USA 89:8641-45 (1992)).

[0019] Exendin-4 potently binds at GLP-1 receptors on insulin-secretingβTC1 cells, at dispersed acinar cells from guinea pig pancreas, and atparietal cells from stomach; the peptide is also said to stimulatesomatostatin release and inhibit gastrin release in isolated stomachs(Goke, et al., J. Biol. Chem. 268:19650-55, 1993; Schepp, et al., Eur.J. Pharmacol., 69:183-91, 1994; Eissele, et al., Life Sci., 55:629-34,1994). Exendin-3 and exendin-4 were reported to stimulate cAMPproduction in, and amylase release from, pancreatic acinar cells(Malhotra, R., et al., Regulatory Peptides,41:149-56, 1992; Raufman, etal., J. Biol. Chem. 267:21432-37, 1992; Singh, et al., Regul. Pept.53:47-59, 1994). The use of exendin-3 and exendin-4 as insulinotrophicagents for the treatment of diabetes mellitus and the prevention ofhypoglycemia has been proposed (Eng, U.S. Pat. No. 5,424,286).

[0020] C-terminally truncated exendin peptides such as exendin-4[9-39],a carboxyamidated molecule, and fragments 3-39 through 9-39 have beenreported to be potent and selective antagonists of GLP-1 (Goke, et al.,J. Biol. Chem., 268:19650-55, 1993; Raufman, J. P., et al., J. Biol.Chem. 266:2897-902, 1991; Schepp, W., et al., Eur. J. Pharm. 269:183-91,1994; Montrose-Rafizadeh, et al., Diabetes, 45(Suppl. 2):152A, 1996).Exendin-4[9-39] is said to block endogenous GLP-1 in vivo, resulting inreduced insulin secretion. Wang, et al., J. Clin. Invest., 95:417-21,1995; D'Alessio, et al., J. Clin. Invest., 97:133-38, 1996). Thereceptor apparently responsible for the insulinotropic effect of GLP-1has reportedly been cloned from rat pancreatic islet cell (Thorens, B.,Proc. Natl. Acad. Sci. USA 89:8641-8645, 1992). Exendins andexendin-4[9-39] are said to bind to the cloned GLP-1 receptor (ratpancreatic β-cell GLP-1 receptor (Fehmann H C, et al., Peptides 15 (3):453-6, 1994) and human GLP-1 receptor (Thorens B, et-al., Diabetes 42(11): 1678-82, 1993). In cells transfected with the cloned GLP-1receptor, exendin-4 is reportedly an agonist, i.e., it increases cAMP,while exendin [9-39] is identified as an antagonist, i.e., it blocks thestimulatory actions of exendin-4 and GLP-1. Id.

[0021] Exendin-4[9-39] is also reported to act as an antagonist of thefull length exendins, inhibiting stimulation of pancreatic acinar cellsby exendin-3 and exendin-4 (Raufman, et al., J. Biol. Chem.266:2897-902, 1991; Raufman, et al., J. Biol. Chem., 266:21432-37,1992). It is also reported that exendin [9-39] inhibits the stimulationof plasma insulin levels by exendin-4, and ownership with the presentinvention and are hereby incorporated by reference.

[0022] Additionally, exendins have been found to suppress glucagonsecretion (U.S. Provisional Application No. ______, entitled, “Methodsfor Glucagon Suppression,” filed Apr. 30, 1999, docket no. 242/168,which enjoys common ownership with the present invention and is herebyincorporated by reference).

[0023] Exendin [9-39] has been used to investigate the physiologicalrelevance of central GLP-1 in control of food intake (Turton, M. D. etal. Nature 379:69-72, 1996). GLP-1 administered byintracerebroventricular injection inhibits food intake in rats. Thissatiety-inducing effect of GLP-1 delivered ICV is reported to beinhibited by ICV injection of exendin [9-391, (Turton, supra). However,it has been reported that GLP-1 does not inhibit food intake in micewhen administered by peripheral injection (Turton, M. D., Nature379:69-72, 1996; Bhavsar, S. P., Soc. Neurosci. Abstr. 21:460 (188.8),1995).

SUMMARY OF THE INVENTION

[0024] The present invention concerns the surprising discovery thatexendins and exendin agonists do not cross the placenta, and yet have aprofound and prolonged effect on blood glucose, rendering them idealagents for the treatment of gestational diabetes mellitus.

[0025] The present invention is directed to novel methods for inhibitsthe somatostatin release-stimulating and gastrin release-inhibitingactivities of exendin-4 and GLP-1 (Kolligs, F., et al., Diabetes,44:16-19, 1995; Eissele, et al., Life Sciences, 55:629-34, 1994).

[0026] Methods for regulating gastrointestinal motility using exendinagonists are described and claimed in U.S. application Ser. No.08/908,867, filed Aug. 8, 1997, entitled, “Methods for RegulatingGastrointestinal Motility,” which application is a continuation-in-partof U.S. application Ser. No. 08/694,954, filed Aug. 8, 1996, whichenjoys common ownership with the present invention and is herebyincorporated by reference.

[0027] Methods of reducing food intake using exendin agonists aredescribed and claimed in U.S. application Ser. No. 09/003,869, filedJan. 7, 1998, entitled, “Use of Exendin and Agonists Thereof for theReduction of Food Intake,” claiming the benefit of ProvisionalApplication Nos. 60/034,905, filed Jan. 7, 1997, 60/055,404, filed Aug.7, 1997, 60/065,442 filed Nov. 14, 1997, and 60/066,029 filed Nov. 14,1997. These applications also enjoy common ownership with the presentinvention and are hereby incorporated by reference.

[0028] Exendins have also been found to have inotropic and diureticeffects. International Application No. PCT/US99/02554, filed Feb. 5,1999, 1998, claiming the benefit of Provisional Application No.60/075,122, filed Feb. 13, 1998. These applications also enjoy commontreating gestational diabetes mellitus comprising the administration ofan exendin, for example, exendin-3 [SEQ ID NO. 1: His Ser Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe IleGlu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser], orexendin-4 [SEQ ID NO. 2: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser LysGln Met. Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly GlyPro Ser Ser Gly Ala Pro Pro Pro Ser], or other compounds whicheffectively bind to the receptor at which exendin exerts its actionswhich are beneficial in the treatment of gestational diabetes mellitus.

[0029] In a first aspect, the invention features a method of treatinggestational diabetes mellitus in a subject comprising administering tothe subject a therapeutically effective amount of an exendin or anexendin agonist. By an “exendin agonist” is meant a compound that mimicsthe effects of exendin in the treatment of gestational diabetes mellitusby binding to the receptor or receptors where exendin causes one or moreof these effects. Exendins and exendin agonists should be especiallybeneficially in the treatment of GDM because, due to their actions toinhibit gastric emptying, administration of such compounds should notresult in increased weight gain. Additionally, in animal and humanstudies to date, administration of exendins and exendin agonists havenot resulted in an increased incidence of hypoglycemia.

[0030] Exendin agonist compounds include exendin acids, for exampleexendin-3 acid and exendin-4 acid. Preferred exendin agonist compoundsinclude those described in International Application No. PCT/US98/16387,entitled, “Novel Exendin Agonist Compounds,” filed Aug. 6, 1998,claiming the benefit of U.S. Provisional Patent Application Serial No.60/055,404, entitled, filed Aug. 8, 1997; International Application No.PCT/US98/24220 entitled, “Novel Exendin Agonist Compounds,” filed Nov.13, 1998, claiming priority on U.S. Provisional Patent ApplicationSerial No. 60/065,442, filed Nov. 14, 1997; and InternationalApplication No. PCT/US98/24273 entitled, “Novel Exendin AgonistCompounds,” filed Nov. 13, 1998, claiming priority on United States U.S.Provisional Patent Application Serial No. 60/066,029, filed Nov. 14,1997; all of which enjoy common ownership with the present applicationand all of which are incorporated by this reference into the presentapplication as though fully set forth herein. Additional preferredexendin agonist compounds are those described and claimed in U.S.Provisional Application Serial No. ______, entitled, “Modified Exendinsand Exendin Agonists,” filed Apr. 30, 1999, docket no. 242/040, whichenjoys common ownership with the present application and which isincorporated by this reference into the present application as thoughfully set forth herein.

[0031] By “gestational diabetes mellitus” or “GDM” is meant any degreeof glucose intolerance with onset or first recognition during pregnancy.

[0032] Thus, in a first embodiment, the present invention provides amethod for treating gestational diabetes in a subject comprisingadministering to said subject a therapeutically effective amount of anexendin or an exendin agonist. Preferred exendin agonist compoundsinclude those described in International Application Nos.PCT/US98/16387, PCT/US98/24220, and PCT/US98/24273, which have beenincorporated by reference in the present application. Preferably, thesubject is a vertebrate, more preferably a mammal, and most preferably ahuman woman. In preferred aspects, the exendin or exendin agonist isadministered parenterally, more preferably by injection. In a mostpreferred aspect, the injection is a peripheral injection. Preferably,about 1 μg-30 μg to about 1 mg of the exendin or exendin agonist isadministered per day. More preferably, about 1-30 μg to about 500 μg, orabout 1-30 μg to about 50 μg of the exendin or exendin agonist isadministered per day. Most preferably, about 3 μg to about 50 μg of theexendin or exendin agonist is administered per day.

[0033] In one preferred aspect, the exendin or exendin agonist used inthe methods of the present invention is exendin-3. In another preferredaspect, said exendin is exendin-4. Other preferred exendin agonistsinclude exendin-4 (1-30) [SEQ ID NO 6: His Gly Glu Gly Thr Phe Thr SerAsp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp LeuLys Asn Gly Gly], exendin4 (1-30) amide [SEQ ID NO 7: His Gly Glu GlyThr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu PheIle Glu Trp Leu Lys Asn Gly Gly-NH₂], exendin-4 (1-28) amide [SEQ ID NO40: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu GluAla Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂], ¹⁴Leu, ²⁵Phe exendin-4amide [SEQ ID NO 9: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer Ser Gly Ala Pro Pro Pro Ser-NH₂], ¹⁴Leu, ²⁵Phe exendin-4 (1-28)amide [SEQ ID NO 41: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂], and¹⁴Leu, ²²Ala, ²⁵Phe exendin-4 (1-28) amide [SEQ ID NO 8: His Gly Glu GlyThr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu AlaIle Glu Phe Leu Lys Asn-NH₂].

[0034] In the methods of the present invention, the exendins and exendinagonists may be administered separately or together with one or moreother compounds and compositions that exhibit a long term or short-termblood glucose control action, including, but not limited to othercompounds and compositions that comprise an insulin or an amylinagonist. Suitable amylin agonists include, for example,[^(25,28,29)Pro-]-human amylin (also known as “pramlintide,” previouslyreferred to as “AC-137,” and, referred to in its acetate salt form byits trademark SYMLIN™ (pramlintide acetate), as described in “AmylinAgonist Peptides and Uses Therefor,” U.S. Pat. No. 5,686,511, issuedNov. 11, 1997, and salmon calcitonin.

BRIEF DESCRIPTION OF THE DRAWINGS

[0035]FIG. 1 depicts the amino acid sequences for certain exendinagonist compounds useful in the present invention [SEQ ID NOS 9-39].

[0036]FIG. 2 depicts concentrations of exendin-4 (AC2993) in plasma andamniotic fluid of rats after 21 μg subcutaneous injection.

[0037]FIG. 3 depicts concentrations of exendin-4 (AC2993) in plasma andamniotic fluid of rats after 210 μg subcutaneous injection.

DETAILED DESCRIPTION OF THE INVENTION

[0038] Exendins and exendin agonists are useful as described herein inview of their pharmacological properties. Activity as exendin agonistscan be indicated by activity in the assays described below. Effects ofexendins or exendin agonists in treating gestational diabetes can beidentified, evaluated, or screened for, using the methods described inthe Examples below, or other methods known in the art for determiningeffects on blood glucose control.

[0039] Exendin Agonist Compounds

[0040] Exendin agonist compounds are those described in InternationalApplication No. PCT/US98/16387, filed Aug. 6, 1998, entitled, “NovelExendin Agonist Compounds,” which claims the benefit of U.S. ProvisionalApplication, No. 60/055,404, filed Aug. 8, 1997, including compounds ofthe formula (I) (SEQ ID NO. 3]:Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Ser Lys Gln Xaa₉ Glu GluGlu Ala Val Arg Leu Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₁₄Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z

[0041] wherein Xaa₁ is His, Arg or Tyr; Xaa₂ is Ser, Gly, Ala or Thr;Xaa₃ is Asp or Glu; Xaa₄ is Phe, Tyr or naphthylalanine; Xaa₅ is Thr orSer; Xaa₆ is Ser or Thr; Xaa₇ is Asp or Glu; Xaa₈ is Leu, Ile, Val,pentylglycine or Met; Xaa₉ is Leu, Ile, pentylglycine, Val or Met; Xaa₁₀is Phe, Tyr or naphthylalanine; Xaa₁₁ is Ile, Val, Leu, pentylglycine,tert-butylglycine or Met; Xaa₁₂ is Glu or Asp; Xaa₁₃ is Trp, Phe, Tyr,or naphthylalanine; Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently Pro,homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine,N-alkylpentylglycine or N-alkylalanine; Xaa₁₈ is Ser, Thr or Tyr; and Zis —OH or —NH₂; with the proviso that the compound is not exendin-3 orexendin-4.

[0042] Preferred N-alkyl groups for N-alkylglycine, N-alkylpentylglycineand N-alkylalanine include lower alkyl groups preferably of 1 to about 6carbon atoms, more preferably of 1 to 4 carbon atoms. Suitable compoundsinclude those listed in FIG. 10 having amino acid sequences of SEQ. ID.NOS. 9 to 39.

[0043] Preferred exendin agonist compounds include those wherein Xaa₁ isHis or Tyr. More preferably Xaa₁ is His.

[0044] Preferred are those compounds wherein Xaa₂ is Gly.

[0045] Preferred are those compounds wherein Xaa₉ is Leu, pentylglycineor Met.

[0046] Preferred compounds include those wherein Xaa₁₃ is Trp or Phe.

[0047] Also preferred are compounds where Xaa₄ is Phe ornaphthylalanine; Xaa₁₁ is Ile or Val and Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇are independently selected from Pro, homoproline, thioproline orN-alkylalanine. Preferably N-alkylalanine has a N-alkyl group-of 1 toabout 6 carbon atoms.

[0048] According to an especially preferred aspect, Xaa₁₅, Xaa₁₆ andXaa₁₇ are the same amino acid reside.

[0049] Preferred are compounds wherein Xaa₁₈ is Ser or Tyr, morepreferably Ser.

[0050] Preferably Z is —NH₂.

[0051] According to one aspect, preferred are compounds of formula (I)wherein Xaa₁ is His or Tyr, more preferably His; Xaa₂ is Gly; Xaa₄ isPhe or naphthylalanine; Xaa₉ is Leu, pentylglycine or Met; Xaa₁₀ is Pheor naphthylalanine; Xaa₁₁ is Ile or Val; Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇are independently selected from Pro, homoproline, thioproline orN-alkylalanine; and Xaa₁₈ is Ser or Tyr, more preferably Ser. Morepreferably Z is —NH₂.

[0052] According to an especially preferred aspect, especially preferredcompounds include those of formula (I) wherein: Xaa₁ is His or Arg; Xaa₂is Gly; Xaa₁ is Asp or Glu; Xaa₄ is Phe or napthylalanine; Xaa₅ is Thror Ser; Xaa₆ is Ser or Thr; Xaa₇ is Asp or Glu; Xaa₈ is Leu orpentylglycine; Xaa₉ is Leu or pentylglycine; Xaa₁₀ is Phe ornaphthylalanine.; Xaa₁₁ is Ile, Val or t-butyltylglycine; Xaa₁₂ is Gluor Asp; Xaa₁₃ is Trp or Phe; Xaa₁₄, Xaa₁₅, Xaa₁₆, and Xaa₁₇ areindependently Pro, homoproline, thioproline, or N-methylalanine; Xaa₁₈is Ser or Tyr: and Z is —OH or —NH₂; with the proviso that the compounddoes not have the formula of either SEQ. ID. NOS. 1 or 2. Morepreferably Z is —NH₂. Especially preferred compounds include thosehaving the amino acid sequence of SEQ. ID. NOS. 9, 10, 21, 22, 23, 26,28, 34, 35 and 39.

[0053] According to an especially preferred aspect, provided arecompounds where Xaa₉ is Leu, Ile, Val or pentylglycine, more preferablyLeu or pentylglycine, and Xaa₁₃ is Phe, Tyr or naphthylalanine, morepreferably Phe or naphthylalanine. These compounds will exhibitadvantageous duration of action and be less subject to oxidativedegradation, both in vitro and in vivo, as well as during synthesis ofthe compound.

[0054] Exendin agonist compounds also include those described inInternational Application No. PCT/US98/24210, filed Nov. 13, 1998,entitled, “Novel Exendin Agonist compounds,” which claims the benefit ofU.S. Provisional Application No. 60/065,442, filed Nov. 14, 1997,including compounds of the formula (II) [SEQ ID NO. 4]: Xaa₁ Xaa₂ Xaa₃Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ Xaa₂₇Xaa₂₈-Z₁; wherein

[0055] Xaa₁ is His, Arg or Tyr;

[0056] Xaa₂ is Ser, Gly, Ala or Thr;

[0057] Xaa₃ is Asp or Glu;

[0058] Xaa₅ is Ala or Thr;

[0059] Xaa₆ is Ala, Phe, Tyr or naphthylalanine;

[0060] Xaa₇ is Thr or Ser;

[0061] Xaa₈ is Ala, Ser or Thr;

[0062] Xaa₉ is Asp or Glu;:

[0063] Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met;

[0064] Xaa₁₁ is Ala or Ser;

[0065] Xaa₁₂ is Ala or Lys;,

[0066] Xaa₁₃ is Ala or Gln;

[0067] Xaa₁₄ is Ala, Leu, Ile, pentylglycine, Val or Met;

[0068] Xaa₁₅ is Ala or Glu;

[0069] Xaa₁₆ is Ala or Glu;

[0070] Xaa₁₇ is Ala or Glu;

[0071] Xaa₁₉ is Ala or Val;

[0072] Xaa₂₀ is Ala or Arg;

[0073] Xaa₂₁ is Ala or Leu;

[0074] Xaa₂₂ is Ala, Phe, Tyr or naphthylalanine;

[0075] Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

[0076] Xaa₂₄ is Ala, Glu or Asp;

[0077] Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine;

[0078] Xaa₂₆ is Ala or Leu;

[0079] Xaa₂₇ is Ala or Lys;

[0080] Xaa₂₈ is Ala or Asn;

[0081] Z₁ is —OH,

[0082] —NH₂

[0083] Gly-Z₂,

[0084] Gly Gly-Z₂,

[0085] Gly Gly Xaa₃₁-Z₂,

[0086] Gly Gly Xaa₃₁ Ser-Z₂,

[0087] Gly Gly Xaa₃₁ Ser Ser-Z₂,

[0088] Gly Gly Xaa₃₁ Ser Ser Gly-Z₂,

[0089] Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂,

[0090] Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂,

[0091] Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇-Z₂ or

[0092] Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂;

[0093] Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently Pro, homoproline,3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine orN-alkylalanine; and

[0094] Z₂ is —OH or —NH₂;

[0095] provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈,Xaa₁₀, Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀,Xaa₂₁, Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₆ are Ala. Preferred N-alkylgroups for N-alkylglycine, N-alkylpentylglycine and N-alkylalanineinclude lower alkyl groups preferably of 1 to about 6 carbon atoms, morepreferably of 1 to 4 carbon atoms.

[0096] Preferred exendin agonist compounds include those wherein Xaa₁ isHis or Tyr. More preferably Xaa₁ is His.

[0097] Preferred are those compounds wherein Xaa₂ is Gly.

[0098] Preferred are those compounds wherein Xaa₁₄ is Leu, pentylglycineor Met.

[0099] Preferred compounds are those wherein Xaa₂₅ is Trp or Phe.

[0100] Preferred compounds are those where Xaa₆ is Phe ornaphthylalanine; Xaa₂₂ is Phe or naphthylalanine and Xaa₂₃ is Ile orVal.

[0101] Preferred are compounds wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ areindependently selected from Pro, homoproline, thioproline andN-alkylalanine.

[0102] Preferably Z₁ is —NH₂.

[0103] Preferable Z₂ is —NH₂.

[0104] According to one aspect, preferred are compounds of formula (II)wherein Xaa₁ is His or Tyr, more preferably His; Xaa₂ is Gly; Xaa₆ isPhe or naphthylalanine; Xaa₁₄ is Leu, pentylglycine or Met; Xaa₂₂ is Pheor naphthylalanine; Xaa₂₃ is Ile or Val; Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈are independently selected from Pro, homoproline, thioproline orN-alkylalanine. More preferably Z₁ is —NH₂.

[0105] According to an especially preferred aspect, especially preferredcompounds include those of formula (II) wherein: Xaa₁ is His or Arg;Xaa₂ is Gly or Ala; Xaa₃ is Asp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala,Phe or nephthylalaine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr; Xaa₉is Asp or Glu; Xaa₁₀ is Ala, Leu or pentylglycine; Xaa₁₁ is Ala or Ser;Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ is Ala, Leu orpentylglycine; Xaa₁₅ is Ala or Glu; Xaa₁₆ is Ala or Glu; Xaa₁₇ is Ala orGlu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala or Arg; Xaa₂₁ is Ala or Leu;Xaa₂₂ is Phe or naphthylalanine; Xaa₂₃ is Ile, Val or tert-butylglycine;Xaa₂₄ is Ala, Glu or Asp; Xaa₂₅ is Ala, Trp or Phe; Xaa₂₆ is Ala or Leu;Xaa₂₇ is Ala or Lys; Xaa₂₈ is Ala or Asn; Z₁ is —OH, —NH₂, Gly-Z₂, GlyGly-Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly Gly Xaa₃₁ SerSer-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂,Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly AlaXaa₃₆ Xaa₃₇-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂;Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ being independently Pro homoproline,thioproline or N-methylalanine; and Z₂ being —OH or —NH₂; provided thatno more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀, Xaa₁₁, Xaa₁₂,Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅,Xaa₂₆, Xaa₂₇, and Xaa₂₈ are Ala. Especially preferred compounds includethose having the amino acid sequence of SEQ. ID. NOS. 40-61.

[0106] According to an especially preferred aspect, provided arecompounds where Xaa₁₄ is Leu, Ile, Val or pentylglycine, more preferablyLeu or pentylglycine, and Xaa₂₅ is Phe, Tyr or naphthylalanine, morepreferably Phe or naphthylalanine. These compounds will be lesssusceptive to oxidative degration, both in vitro and in vivo, as well asduring

[0107] Synthesis of the Compound.

[0108] Exendin agonist compounds also include those described inInternational Patent Application No. PCT/US98/24273, filed Nov. 13,1998, entitled, “Novel Exendin Agonist Compounds,” which claims thebenefit of U.S. Provisional Application No. 60/066,029, filed Nov. 14,1997, including compounds of the formula (III) [SEQ ID NO. 5]: Xaa₁ Xaa₂Xaa₃ Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅Xaa₁₆ Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ Xaa₂₇Xaa₂₈- Z₁; wherein

[0109] Xaa₁ is His, Arg, Tyr, Ala, Norval, Val or Norleu;

[0110] Xaa₂ is Ser, Gly, Ala or Thr;

[0111] Xaa₃ is Ala, Asp or Glu;

[0112] Xaa₄ is Ala, Norval, Val, Norleu or Gly;

[0113] Xaa₅ is Ala or Thr;

[0114] Xaa₆ is Phe, Tyr or naphthylalanine;

[0115] Xaa₇ is Thr or Ser;

[0116] Xaa₈ is Ala, Ser or Thr;

[0117] Xaa₉ is Ala, Norval, Val, Norleu, Asp or Glu;

[0118] Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met;

[0119] Xaa₁₁ is Ala or Ser;

[0120] Xaa₁₂ is Ala or Lys;

[0121] Xaa₁₃ is Ala or Gln;

[0122] Xaa₁₄ is Ala, Leu, Ile, pentylglycine, Val or Met;

[0123] Xaa₁₅ is Ala or Glu;

[0124] Xaa₁₆ is Ala or Glu;

[0125] Xaa₁₇ is Ala or Glu;

[0126] Xaa₁₉ is Ala or Val;

[0127] Xaa₂₀ is Ala or Arg;

[0128] Xaa₂₁ is Ala or Leu;

[0129] Xaa₂₂ is Phe, Tyr or naphthylalanine;

[0130] Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

[0131] Xaa₂₄ is Ala, Glu or Asp;

[0132] Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine;

[0133] Xaa₂₆ is Ala or Leu;

[0134] Xaa₂₇ is Ala or Lys;

[0135] Xaa₂₈ is Ala or Asn;

[0136] Z₁ is —OH,

[0137] —NH₂,

[0138] Gly-Z₂,

[0139] Gly Gly-Z₂,

[0140] Gly Gly Xaa₃₁-Z₂,

[0141] Gly Gly Xaa₃₁ Ser-Z₂,

[0142] Gly Gly Xaa₃₁ Ser Ser-Z₂,

[0143] Gly Gly Xaa₃₁ Ser Ser Gly-Z₂,

[0144] Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂,

[0145] Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂,

[0146] Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ -Z₂,

[0147] Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂ or Gly GlyXaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈ Xaa₃₉-Z₂; wherein

[0148] Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently Pro, homoproline,3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine orN-alkylalanine; and,

[0149] Z₂ is —OH or —NH₂;

[0150] provided that no more than three of Xaa₃₁ Xaa₄, Xaa₅, Xaa₆, Xaa₈,Xaa₉, Xaa₁₀, Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉,Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala; and providedalso that, if Xaa₁ is His, Arg or Tyr, then at least one of Xaa₃, Xaa₄and Xaa₉ is Ala.

[0151] Definitions

[0152] In accordance with the present invention and as used herein, thefollowing terms are defined to have the following meanings, unlessexplicitly stated otherwise.

[0153] The term “amino acid” refers to natural amino acids, unnaturalamino acids, and amino acid analogs, all in their D and L stereoisomersif their structure allow such stereoisomeric forms. Natural amino acidsinclude alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid(Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine(Gly), histidine (His), isoleucine (Ile), leucine (Leu), Lysine (Lys),methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser),threonine (Thr), typtophan (Trp), tyrosine (Tyr) and valine (Val).Unnatural amino acids include, but are not limited toazetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid,beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyricacid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyricacid, 3-aminoisbutyric acid, 2-aminopimelic acid, tertiary-butylglycine,2,4-diaminoisobutyric acid, desmosine, 2,2′-diaminopimelic acid,2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine,homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline,4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine,N-methylglycine, N-methylisoleucine, N-methylpentylglycine,N-methylvaline, naphthalanine, norvaline, norleucine, ornithine,pentylglycine, pipecolic acid and thioproline. Amino acid analogsinclude the natural and unnatural amino acids which are chemicallyblocked, reversibly or irreversibly, or modified on their N-terminalamino group or their side-chain groups, as for example, methioninesulfoxide, methionine sulfone, S-(carboxymethyl)-cysteine,S-(carboxymethyl)-cysteine sulfoxide and S-(carboxymethyl)-cysteinesulfone.

[0154] The term “amino acid analog” refers to an amino acid whereineither the C-terminal carboxy group, the N-terminal amino group orside-chain functional group has been chemically codified to anotherfunctional group. For example, aspartic acid-(beta-methyl ester) is anamino acid analog of aspartic acid; N-ethylglycine is an amino acidanalog of glycine; or alanine carboxamide is an amino acid analog ofalanine.

[0155] The term “amino acid residue” refers to radicals having thestructure: (1) —C(O)—R—NH—, wherein R typically is —CH(R′)—, wherein R′is an amino acid side chain, typically H or a carbon containingsubstitutent; or (2)

[0156] wherein p is 1, 2 or 3 representing the azetidinecarboxylic acid,proline or pipecolic acid residues, respectively.

[0157] The term “lower” referred to herein in connection with organicradicals such as alkyl groups defines such groups with up to andincluding about 6, preferably up to and including 4 and advantageouslyone or two carbon atoms. Such groups may be straight chain or branchedchain.

[0158] “Pharmaceutically acceptable salt” includes salts of thecompounds described herein derived from the combination of suchcompounds and an organic or inorganic acid. In practice the use of thesalt form amounts to use of the base form. The compounds are useful inboth free base and salt form.

[0159] In addition, the following abbreviations stand for the following:

[0160] “ACN” or “CH₃CN” refers to acetonitrile.

[0161] “Boc”, “tBoc” or “Tboc” refers to t-butoxy carbonyl.

[0162] “DCC” refers to N,N′-dicyclohexylcarbodiimide.

[0163] “Fmoc” refers to fluorenylmethoxycarbonyl.

[0164] “HBTU” refers to2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexaflurophosphate.

[0165] “HOBt” refers to 1-hydroxybenzotriazole monohydrate.

[0166] “homoP” or hpro” refers to homoproline.

[0167] “MeAla” or “Nme” refers to N-methylalanine.

[0168] “naph” refers to naphthylalanine.

[0169] “pG” or pGly” refers to pentylglycine.

[0170] “tBuG” refers to tertiary-butylglycine.

[0171] “ThioP” or tPro” refers to thioproline.

[0172] 3Hyp” refers to 3-hydroxyproline

[0173] 4Hyp” refers to 4-hydroxyproline

[0174] NAG” refers to N-alkylglycine

[0175] NAPG” refers to N-alkylpentylglycine

[0176] “Norval” refers to norvaline

[0177] “Norleu” refers to norleucine

[0178] Preparation of Compounds

[0179] The exendins and exendin agonists described herein may beprepared using standard solid-phase peptide synthesis techniques andpreferably an automated or semiautomated peptide synthesizer. Typically,using such techniques, an α-N-carbamoyl protected amino acid and anamino acid attached to the growing peptide chain on a resin are coupledat room temperature in an inert solvent such as dimethylformamide,N-methylpyrrolidinone or methylene chloride in the presence of couplingagents such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole inthe presence of a base such as diisopropylethylamine. The α-N-carbamoylprotecting group is removed from the resulting peptide-resin using areagent such as trifluoroacetic acid or piperidine, and the couplingreaction repeated with the next desired N-protected amino acid to beadded to the peptide chain. Suitable N-protecting groups are well knownin the art, with t-butyloxycarbonyl (tBoc) and fluorenylmethoxycarbonyl(Fmoc) being preferred herein.

[0180] The solvents, amino acid derivatives and 4-methylbenzhydryl-amineresin used in the peptide synthesizer may be purchased from AppliedBiosystems Inc. (Foster City, Calif.). The following side-chainprotected amino acids may be purchased from Applied Biosystems, Inc.:Boc-Arg(Mts), Fmoc-Arg(Pmc), Boc-Thr(Bzl), Fmoc-Thr(t-Bu), Boc-Ser(Bzl),Fmoc-Ser(t-Bu), Boc-Tyr(BrZ), Fmoc-Tyr(t-Bu), Boc-Lys(Cl-Z),Fmoc-Lys(Boc) Boc-Glu(Bzl), Fmoc-Glu(t-Bu), Fmoc-His(Trt),Fmoc-Asn(Trt), and Fmoc-Gln(Trt). Boc-His(BOM) may be purchased fromApplied Biosystems, Inc. or Bachem Inc. (Torrance, Calif.). Anisole,dimethylsulfide, phenol, ethanedithiol, and thioanisole may be obtainedfrom Aldrich Chemical Company (Milwaukee, Wis). Air Products andChemicals (Allentown, Pa.) supplies HF. Ethyl ether, acetic acid andmethanol may be purchased from Fisher Scientific (Pittsburgh, Pa.).

[0181] Solid phase peptide synthesis may be carried out with anautomatic peptide synthesizer (Model 430A, Applied Biosystems Inc.,Foster City, Calif.) using the NMP/HOBt (Option 1) system and tBoc orFmoc chemistry (see, Applied Biosystems User's Manual for the ABI 430APeptide Synthesizer, Version 1.3B Jul. 1, 1988, section 6, pp. 49-70,Applied Biosystems, Inc., Foster City, Calif.) with capping.Boc-peptide-resins may be cleaved with HF (−5° C. to 0° C., 1 hour). Thepeptide may be extracted from the resin with alternating water andacetic acid, and the filtrates lyophilized. The Fmoc-peptide resins maybe cleaved according to standard methods (Introduction to CleavageTechniques, Applied Biosystems, Inc., 1990, pp. 6-12). Peptides may bealso be assembled using an Advanced Chem Tech Synthesizer (Model MPS350, Louisville, Ky.).

[0182] Peptides may be purified by RP-HPLC (preparative and analytical)using a Waters Delta Prep 3000 system. A C4, C8 or C18 preparativecolumn (10μ, 2.2×25 cm; Vydac, Hesperia, Calif.) may be used to isolatepeptides, and purity may be determined using a C4, C8 or C18 analyticalcolumn (5μ, 0.46×25 cm; Vydac). Solvents (A=0.1% TFA/water and B=0.1%TFA/CH₃CN) may be delivered to the analytical column at a flowrate of1.0 ml/min and to the preparative column at 15 ml/min. Amino acidanalyses may be performed on the Waters Pico Tag system and processedusing the Maxima program. Peptides may be hydrolyzed by vapor-phase acidhydrolysis (115° C., 20-24 h). Hydrolysates may be derivatized andanalyzed by standard methods (Cohen, et al., The Pico Tag Method: AManual of Advanced Techniques for Amino Acid Analysis, pp. 11-52,Millipore Corporation, Milford, Mass. (1989)). Fast atom bombardmentanalysis may be carried out by M-Scan, Incorporated (West Chester, Pa.).Mass calibration may be performed using cesium iodide or cesiumiodide/glycerol. Plasma desorption ionization analysis using time offlight detection may be carried out on an Applied Biosystems Bio-Ion 20mass spectrometer. Electrospray mass spectroscopy may be carried out ona VG-Trio machine.

[0183] Peptide compounds useful in the invention may also be preparedusing recombinant DNA techniques, using methods now known in the art.See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2dEd., Cold Spring Harbor (1989). Non-peptide compounds useful in thepresent invention may be prepared by art-known methods. For example,phosphate-containing amino acids and peptides containing such aminoacids, may be prepared using methods known in the art. See, e.g.,Bartlett and Landen, Biorg. Chem. 14:356-377 (1986)

[0184] Compositions useful in the invention may conveniently be providedin the form of formulations suitable for parenteral (includingintravenous, intramuscular and subcutaneous) or nasal or oraladministration. In some cases, it will be convenient to provide anexendin or exendin agonist and another blood glucose-controlling, plasmaglucose-lowering agent, such as an insulin, an amylin, an amylinagonist, in a single composition or solution for administrationtogether. In other cases, it may be more advantageous to administer theadditional agent separately from said exendin or exendin agonist. Asuitable administration format may best be determined by a medicalpractitioner for each patient individually. Suitable pharmaceuticallyacceptable carriers and their formulation are described in standardformulation treatises, e.g., Remington's Pharmaceutical Sciences by E.W. Martin. See also Wang, Y. J. and Hanson, M. A. “ParenteralFormulations of Proteins and Peptides: Stability and Stabilizers,”Journal of Parenteral Science and Technology, Technical Report No. 10,Supp. 42:2S (1988).

[0185] Compounds useful in the invention can be provided as parenteralcompositions for injection or infusion. Preferred formulations are thosedescribed and claimed in U.S. application Ser. No. 60/116,380, entitled,“Novel Exendin Agonist Formulations and Methods of AdministrationThereof,” filed Jan. 14, 1999, which enjoys common ownership with thepresent application and which is incorporated by this reference into thepresent application as though fully set forth herein. They can, forexample, be suspended in an inert oil, suitably a vegetable oil such assesame, peanut, olive oil, or other acceptable carrier. Preferably, theyare suspended in an aqueous carrier, for example, in an isotonic buffersolution at a pH of about 3.0 to 8.0, preferably at a pH of about 3.5 to5.0. These compositions may be sterilized by conventional sterilizationtechniques, or may be sterile filtered. The compositions may containpharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions, such as pH buffering agents.Useful buffers include for example, sodium acetate/acetic acid buffers.A form of repository or “depot” slow release preparation may be used sothat therapeutically effective amounts of the preparation are deliveredinto the bloodstream over many hours or days following transdermalinjection or delivery.

[0186] The desired isotonicity may be accomplished using sodium chlorideor other pharmaceutically acceptable agents such as dextrose, boricacid, sodium tartrate, propylene glycol, polyols (such as mannitol andsorbitol), or other inorganic or organic solutes. Sodium chloride ispreferred particularly for buffers containing sodium ions.

[0187] The claimed compositions can also be formulated aspharmaceutically acceptable salts (e.g., acid addition salts) and/orcomplexes thereof. Pharmaceutically acceptable salts are non-toxic saltsat the concentration at which they are administered. The preparation ofsuch salts can facilitate the pharmacological use by altering thephysical-chemical characteristics of the composition without preventingthe composition from exerting its physiological effect. Examples ofuseful alterations in physical properties include lowering the meltingpoint to facilitate transmucosal administration and increasing thesolubility to facilitate the administration of higher concentrations ofthe drug.

[0188] Pharmaceutically acceptable salts include acid addition saltssuch as those containing sulfate, hydrochloride, phosphate, sulfamate,acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.Pharmaceutically acceptable salts can be obtained from acids such ashydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, aceticacid, citric acid, lactic acid, tartaric acid, malonic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. Suchsalts may be prepared by, for example, reacting the free acid or baseforms of the product with one or more equivalents of the appropriatebase or acid in a solvent or medium in which the salt is insoluble, orin a solvent such as water which is then removed in vacuo or byfreeze-drying or by exchanging the ions of an existing salt for anotherion on a suitable ion exchange resin.

[0189] Carriers or excipients-can also be used to facilitateadministration of the compound. Examples of carriers and excipientsinclude calcium carbonate, calcium phosphate, various sugars such aslactose, glucose, or sucrose, or types of starch, cellulose derivatives,gelatin, vegetable oils, polyethylene glycols and physiologicallycompatible solvents. The compositions or pharmaceutical composition canbe administered by different routes including intravenously,intraperitoneal, subcutaneous, and intramuscular, orally, topically,transmucosally, or by pulmonary inhalation.

[0190] If desired, solutions of the above compositions may be thickenedwith a thickening agent such as methyl cellulose. They may be preparedin emulsified form, either water in oil or oil in water. Any of a widevariety of pharmaceutically acceptable emulsifying agents may beemployed including, for example, acacia powder, a non-ionic surfactant(such as a Tween), or an ionic surfactant (such as alkali polyetheralcohol sulfates or sulfonates, e.g., a Triton).

[0191] Compositions useful in the invention are prepared by mixing theingredients following generally accepted procedures. For example, theselected components may be simply mixed in a blender or other standarddevice to produce a concentrated mixture which may then be adjusted tothe final concentration and viscosity by the addition of water orthickening agent and possibly a buffer to control pH or an additionalsolute to control tonicity.

[0192] For use by the physician, the compositions will be provided indosage unit form containing an amount of an exendin or exendin agonist,for example, exendin-3, and/or exendin-4, with or without anotherglucosed-lowering agent. Therapeutically effective amounts of an exendinor exendin agonist for use treating a subject with gestational diabetesmellitus are those that lower blood glucose to a desired level. As willbe recognized by those in the field, an effective amount of therapeuticagent will vary with many factors including the age and weight of thepatient, the patient's physical condition, the blood glucose level andother factors.

[0193] The effective daily blood glucose controlling dose of thecompounds will typically be in the range of about 3 to 30 μg to about 1mg/day, preferably about 1 to 30 μg to about 500 μg/day and morepreferably about 1 to 30 μg to about 100 μg/day, most preferably about 3μg to about 50 μg/day, for a 70 kg patient, administered in a single ordivided doses. Preferred dosages are described in U.S. application Ser.No. 60/116,380, entitled, “Novel Exendin Agonist Formulations andMethods of Administration Thereof,” filed Jan. 14, 1999, which has beenincorporated by reference into the present application. A preferred dosefor twice daily administration is about 0.05 to about 0.3 μg perkilogram. The exact dose to be administered is determined by theattending clinician and is dependent upon where the particular compoundlies within the above quoted range, as well as upon the age, weight andcondition of the individual, and the mode of administration.Administration should begin shortly after diagnosis of GDM and continuefor the remainder of the gestation (i.e., the third trimester throughparturition). Administration may be by injection, preferablysubcutaneous or intramuscular. Administration may also be bynon-injectable routes, for example, via the respiratory tract, the mouthand the gut. Orally active compounds may be taken orally, howeverdosages should be increased 5-10 fold. Preferred methods ofadministration are described in U.S. Application Ser. No. 60/116,380,entitled, “Novel Exendin Agonist Formulations and Methods ofAdministration Thereof,” filed Jan. 14, 1999, which has beenincorporated by reference into the present application. Solid dosageforms, such as those useful for oral, buccal, sublingual,intra-tracheal, nasal or pulmonary delivery may be used. Additionally,preserved or unpreserved liquid formulations or dry powder may be used

[0194] The optimal formulation and mode of administration of compoundsof the present application to a patient depend on factors known in theart such as the particular disease or disorder, the desired effect, andthe type of patient. While the compounds will typically be used to treathuman subjects they may also be used to treat similar or identicaldiseases in other vertebrates such as other primates, farm animals suchas swine, cattle and poultry, and sports animals and pets such ashorses, dogs and cats.

[0195] To assist in understanding the present invention, the followingExamples are included. The experiments relating to this invention shouldnot, of course, be construed as specifically limiting the invention andsuch variations of the invention, now known or later developed, whichwould be within the purview of one skilled in the art are considered tofall within the scope of the invention as described herein andhereinafter claimed.

EXAMPLE 1

[0196] Preparation of Amidated Peptide Having SEQ. ID. NO. 9

[0197] The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.). In general, single-coupling cycles were usedthroughout the synthesis and Fast Moc (HBTU activation) chemistry wasemployed. However, at some positions coupling was less efficient thanexpected and double couplings were required. In particular, residuesAsp₉, Thr, and Phe₆ all required double coupling. Deprotection (Fmocgroup removal) of the growing peptide chain using piperidine was notalways efficient. Double deprotection was required at positions Arg₂₀,Val₁₉ and Leu₁₄. Final deprotection of the completed peptide resin wasachieved using a mixture of triethylsilane (0.2 mL), ethanedithiol (0.2mL), anisole (0.2 mL), water (0.2 mL) and trifluoroacetic acid (15 mL)according to standard methods (Introduction to Cleavage Techniques,Applied Biosystems, Inc.) The peptide was precipitated in ether/water(50 mL) and centrifuged. The precipitate was reconstituted in glacialacetic acid and lyophilized. The lyophilized peptide was dissolved inwater). Crude purity was about 55%.

[0198] Used in purification steps and analysis were Solvent A (0.1% TFAin water) and Solvent B (0.1% TFA in ACN).

[0199] The solution containing peptide was applied to a preparative C-18column and purified (10% to 40% Solvent B in Solvent A over 40 minutes).Purity of fractions was determined isocratically using a C-18 analyticalcolumn. Pure fractions were pooled furnishing the above-identifiedpeptide. Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide gave product peptide havingan observed retention time of 14.5 minutes. Electrospray MassSpectrometry (M): calculated 4131.7; found 4129.3.

EXAMPLE 2

[0200] Preparation of Peptide Having SEQ. ID. NO. 10

[0201] The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 5. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 25% to 75% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 21.5 minutes. Electrospray Mass Spectrometry (M): calculated4168.6; found

EXAMPLE 3

[0202] Preparation of Peptide Having SEQ. ID. NO. 11

[0203] The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.9 minutes. Electrospray Mass Spectrometry (M): calculated4147.6; found 4150.2.

EXAMPLE 3

[0204] Preparation of Peptide Having SEQ. ID. NO. 12

[0205] The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 65% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 19.7 minutes. Electrospray Mass Spectrometry (M): calculated4212.6; found 4213.2.

EXAMPLE 4

[0206] Preparation of Peptide Having SEQ. ID. NO. 13

[0207] The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 50% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 16.3 minutes. Electrospray Mass Spectrometry (M): calculated4262.7; found 4262.4.

EXAMPLE 5

[0208] Preparation of Peptide Having SEQ. ID. NO. 14

[0209] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4172.6

EXAMPLE 6

[0210] Preparation of Peptide Having SEQ. ID. NO. 15

[0211] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4224.7.

EXAMPLE 7

[0212] Preparation of Peptide Having SEQ. ID. NO. 16

[0213] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4172.6

EXAMPLE 8

[0214] Preparation of Peptide Having SEQ. ID. NO. 17

[0215] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4186.6

EXAMPLE 9

[0216] Preparation of Peptide Having SEQ. ID. NO. 18

[0217] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4200.7

EXAMPLE 10

[0218] Preparation of Peptide Having SEQ. ID. NO. 19.

[0219] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4200.7

EXAMPLE 11

[0220] Preparation of Peptide Having SEQ. ID. NO. 20

[0221] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4202.7.

EXAMPLE 12

[0222] Preparation of Peptide Having SEQ. ID. NO. 21

[0223] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4145.6.

EXAMPLE 13

[0224] Preparation of Peptide Having SEQ. ID. NO. 22

[0225] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then f carried out to determine the retentiontime of the product peptide. Electrospray Mass Spectrometry (M):calculated 4184.6.

EXAMPLE 14

[0226] Preparation of Peptide Having SEQ. ID. NO. 23

[0227] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4145.6.

EXAMPLE 15

[0228] Preparation of Peptide Having SEQ. ID. NO; 24

[0229] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4224.7.

EXAMPLE 16

[0230] Preparation of Peptide Having SEQ. ID. NO. 25

[0231] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin; deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4172.6.

EXAMPLE 17

[0232] Preparation of Peptide Having SEQ. ID. NO. 26

[0233] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4115.5.

EXAMPLE 18

[0234] Preparation of Peptide Having SEQ. ID. NO. 27

[0235] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in.water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to,60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4188.6.

EXAMPLE 19

[0236] Preparation of Peptide Having SEQ. ID. NO. 28

[0237] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4131.6.

EXAMPLE 20

[0238] Preparation of Peptide Having SEQ. ID. NO. 29

[0239] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4172.6.

EXAMPLE 21

[0240] Preparation of Peptide Having SEQ. ID. NO. 30

[0241] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4145.6.

EXAMPLE 22

[0242] Preparation of Peptide Having SEQ. ID. NO. 31

[0243] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the thioproline positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 4266.8.

EXAMPLE 23

[0244] Preparation of Peptide Having SEQ. ID. NO. 32

[0245] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55.mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the thioproline positions 38, 37 and 36. Used in analysisare Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA in ACN).Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30minutes) of the lyophilized peptide is then carried out to determine theretention time of the product peptide. Electrospray Mass Spectrometry(M): calculated 4246.9.

EXAMPLE 24

[0246] Preparation of Peptide Having SEQ. ID. NO. 33

[0247] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the homoproline positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M) : calculated 4250.8.

EXAMPLE 25

[0248] Preparation of Peptide Having SEQ. ID. NO. 34

[0249] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the homoproline positions 38, 37, and 36. Used in analysisare Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA in ACN).Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30minutes) of the lyophilized peptide is then carried out to determine theretention time of the product peptide. Electrospray Mass Spectrometry(M): calculated 4234.8.

EXAMPLE 26

[0250] Preparation of Peptide Having SEQ. ID. NO. 35

[0251] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the thioproline positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 4209.8.

EXAMPLE 27

[0252] Preparation of Peptide Having SEQ. ID. NO. 36

[0253] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the homoproline positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 4193.7.

EXAMPLE 28

[0254] Preparation of Peptide Having SEQ. ID. NO. 37

[0255] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example l. Additional double couplings arerequired at the N-methylalanine positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3858.2.

EXAMPLE 29

[0256] Preparation of Peptide Having SEQ. ID. NO. 38

[0257] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from-the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the N-methylalanine positions 38, 37 and 36. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3940.3.

EXAMPLE 30

[0258] Preparation of Peptide Having SEQ. ID. NO. 39

[0259] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the N-methylalanine positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes of the lyophilized paptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3801.1.

EXAMPLE 31

[0260] Preparation of C-Terminal Carboxylic Acid Peptides Correspondingto the Above C-Terminal Amide Sequences.

[0261] The above peptides of Examples 1-5 to 30 are assembled on the socalled Wang resin (p-alkoxybenzylalacohol resin (Bachem, 0.54 mmole/g))using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleavedfrom the resin, deprotected and purified in a similar way to Example 1.Used in analysis are Solvent A (0.1% TFA in water) and Solvent B (0.1%TFA in ACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B inSolvent A over 30 minutes) of the lyophilized peptide is then carriedout to determine the retention time of the product peptide. ElectrosprayMass Spectrometry provides an experimentally determined (M).

EXAMPLE 32

[0262] Preparation of Peptide Having SEQ ID NO. 7 [SEQ. ID. NO. 7] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH ₂

[0263] The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using. Fmoc-protected amino acids(Applied Biosystems, Inc.). In general, single-coupling cycles were usedthroughout the synthesis and Fast Moc (HBTU activation) chemistry wasemployed. Deprotection (Fmoc group removal) of the growing peptide chainwas achieved using piperidine. Final deprotection of the completedpeptide resin was achieved using a mixture of triethylsilane (0.2 mL),ethanedithiol (0.2 mL), anisole (0.2 mL), water (0.2 mL) andtrifluoroacetic acid (15 mL) according to standard methods (Introductionto Cleavage Techniques, Applied Biosystems, Inc.) The peptide wasprecipitated in ether/water (50 mL) and centrifuged. The precipitate wasreconstituted in glacial acetic acid and lyophilized. The lyophilizedpeptide was dissolved in water). Crude purity was about 75%.

[0264] Used in purification steps and analysis were Solvent A (0.1% TFAin water) and Solvent B (0.1% TFA in ACN). The solution containingpeptide was applied to a preparative C-18 column and purified (10% to40% Solvent B in Solvent A over 40 minutes). Purity of fractions wasdetermined isocratically using a C-18 analytical column. Pure fractionswere pooled furnishing the above-identified peptide. Analytical RP-HPLC(gradient 30% to 50% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 18.9 minutes. Electrospray Mass Spectrometry (M): calculated3408.0; found 3408.9.

EXAMPLE 33

[0265] Preparation of Peptide Having SEQ ID NO. 40 [SEQ. ID. NO. 40] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0266] The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 40% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.9 minutes. Electrospray Mass Spectrometry (M): calculated3294.7; found 3294.8.

EXAMPLE 34

[0267] Preparation of Peptide Having SEQ ID NO. 41 [SEQ. ID. NO. 41] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0268] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 29% to 36% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 20.7 minutes. Electrospray Mass Spectrometry (M): calculated3237.6; found 3240.

EXAMPLE 35

[0269] Preparation of Peptide Having SEQ ID NO. 42 [SEQ. ID. NO. 42] HisAla Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0270] The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 15.2 minutes. Electrospray Mass-Spectrometry (M): calculated3251.6; found 3251.5.

EXAMPLE 36

[0271] Preparation of Peptide Having SEQ ID NO. 43 [SEQ. ID. NO. 43] HisGly Glu Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0272] The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and:Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 13.1 minutes. Electrospray Mass Spectrometry (M): calculated3207.6; found 3208.3.

EXAMPLE 37

[0273] Preparation of Peptide Having SEQ ID NO. 44 [SEQ. ID. NO. 44] HisGly Glu Gly Thr Ala Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0274] The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 12.8 minutes. Electrospray Mass Spectrometry (M): calculated3161.5; found 3163.

EXAMPLE 38

[0275] Preparation of Peptide Having SEQ ID NO. 45

[0276] His Gly Glu Gly Thr Phe Thr Ala Asp Leu Ser Lys Gln Leu Glu GluGlu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂ [SEQ. ID. NO. 45]

[0277] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 15.2 minutes. Electrospray Mass Spectrometry (M): calculated3221.6; found 3222.7.

EXAMPLE 39

[0278] Preparation of Peptide Having SEQ ID NO. 46 [SEQ. ID. NO. 46] HisGly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0279] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 34% to 44% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.3 minutes. Electrospray Mass Spectrometry (M): calculated3195.5; found 3199.4.

EXAMPLE 40

[0280] Preparation of Peptide Having SEQ ID NO. 47 [SEQ. ID. NO. 47] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ala Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0281] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using, Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 15.7 minutes. Electrospray Mass Spectrometry (M): calculated3221.6; found 3221.6.

EXAMPLE 41

[0282] Preparation of Peptide Having SEQ ID NO. 48 [SEQ. ID. NO. 48] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

[0283] The above-identified amidated peptide was assembled on4-(21-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 18.1 minutes. Electrospray Mass Spectrometry (M): calculated3180.5; found 3180.9.

EXAMPLE 42

[0284] Preparation of Peptide Having SEQ ID NO. 49 [SEQ. ID. NO. 49] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0285] The above-identified amidated peptide was assembled on4-2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.0 minutes. Electrospray Mass Spectrometry (M): calculated3180.6; found 3182.8.

EXAMPLE 43

[0286] Preparation of Peptide Having SEQ ID NO. 50 [SEQ. ID. NO. 50] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Ala Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0287] The above-identified amidated peptide was assembled on4-(21-4,-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino:acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 32% to 42% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.9 minutes. Electrospray Mass Spectrometry (M): calculated3195.5; found 3195.9.

EXAMPLE 44

[0288] Preparation of Peptide Having SEQ ID NO. 51 [SEQ. ID. NO. 51] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Ala Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0289] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.9 minutes. Electrospray Mass Spectrometry (M): calculated3179.6; found 3179.0.

EXAMPLE 45

[0290] Preparation of Peptide Having SEQ ID NO. 52 [SEQ. ID. NO. 52] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Ala Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0291] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.3 minutes. Electrospray Mass Spectrometry (M): calculated3179.6; found 3180.0.

EXAMPLE 46

[0292] Preparation of Peptide Having SEQ ID NO. 53 [SEQ. ID. NO. 53] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Ala Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0293] The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 13.7 minutes. Electrospray Mass Spectrometry (M): calculated3179.6; found 3179.0.

EXAMPLE 47

[0294] Preparation of Peptide Having SEQ ID NO. 54 [SEQ. ID. NO. 54] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala AlaArg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0295] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.0 minutes. Electrospray Mass Spectrometry (M): calculated3209.6; found 3212.8.

EXAMPLE 48

[0296] Preparation of Peptide Having SEQ ID NO. 55 [SEQ. ID. NO. 55] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValAla Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0297] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in-water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide.having an observed retentiontime of 14.3 minutes. Electrospray Mass Spectrometry (M): calculated3152.5; found 3153.5.

EXAMPLE 49

[0298] Preparation of Peptide Having SEQ ID NO. 56 [SEQ. ID. NO. 56] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Ala Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0299] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave. product peptide having an observed retentiontime of 12.1 minutes. Electrospray Mass Spectrometry (M): calculated3195.5; found 3197.7.

EXAMPLE 50

[0300] Preparation of Peptide Having SEQ ID NO. 57 [SEQ. ID. NO. 57] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Ala Phe Leu Lys Asn-NH ₂

[0301] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 10.9 minutes. Electrospray Mass Spectrometry (M): calculated3179.6; found 3180.5.

EXAMPLE 51

[0302] Preparation of Peptide Having SEQ ID NO. 58 [SEQ. ID. NO. 58] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Ala Leu Lys Asn-NH ₂

[0303] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 32% to 42% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.5 minutes. Electrospray Mass Spectrometry (M): calculated3161.5; found 3163.0.

EXAMPLE 52

[0304] Preparation of Peptide Having SEQ ID NO. 59 [SEQ. ID. NO. 59] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Ala Lys Asn-NH ₂

[0305] The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 32% to 42% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 19.5 minutes. Electrospray Mass Spectrometry (M): calculated3195.5; found 3199.

EXAMPLE 53

[0306] Preparation of Peptide Having SEQ ID NO. 60 [SEQ. ID. NO. 60] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Ala Asn-NH ₂

[0307] The above-identified amidated peptide was assembled on A over 30minutes) of the lyophilized peptide gave product peptide having anobserved retention time of 22.8 minutes. Electrospray Mass Spectrometry(M): calculated 3194.6; found 3197.6.

EXAMPLE 55

[0308] Preparation of Peptide Having SEQ ID NO. 62 [SEQ. ID. NO. 62] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro ProPro-NH ₂

[0309] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4099. 6.

EXAMPLE 56

[0310] Preparation of Peptide Having SEQ ID NO. 63 [SEQ. ID. NO. 63] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro ProPro-NH ₂

[0311] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA-resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4042.5.

EXAMPLE 57

[0312] Preparation of Peptide Having SEQ ID NO. 64 [SEQ. ID. NO. 64] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala ProPro-NH ₂

[0313] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4002.4

EXAMPLE 58

[0314] Preparation of Peptide Having SEQ ID NO. 65 [SEQ. ID. NO. 65] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala ProPro-NH ₂

[0315] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1%, TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3945.4.

EXAMPLE 59

[0316] Preparation of Peptide Having SEQ ID NO. 66 [SEQ. ID. NO. 66] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro-NH ₂

[0317] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3905.3.

EXAMPLE 60

[0318] Preparation of Peptide Having SEQ ID NO. 67 [SEQ. ID. NO. 67] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro-NH ₂

[0319] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3848.2.

EXAMPLE 61

[0320] Preparation of Peptide Having SEQ ID NO. 68 [SEQ. ID. NO. 68] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH ₂

[0321] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3808.2.

EXAMPLE 62

[0322] Preparation of Peptide Having SEQ ID NO. 69 [SEQ. ID. NO. 69] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH ₂

[0323] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3751.1.

EXAMPLE 63

[0324] Preparation of Peptide Having SEQ ID NO. 70 [SEQ. ID. NO. 70] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly-NH ₂

[0325] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3737.1.

EXAMPLE 64

[0326] Preparation of Peptide Having SEQ ID NO. 71 [SEQ. ID. NO. 71] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly-NH ₂

[0327] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3680.1.

EXAMPLE 65

[0328] Preparation of Peptide Having SEQ ID NO. 72 [SEQ. ID. NO. 72] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser-NH ₂

[0329] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3680.1

EXAMPLE 66

[0330] Preparation of Peptide Having SEQ ID NO. 73 [SEQ. ID. NO. 73] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser-NH ₂

[0331] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3623.0.

EXAMPLE 67

[0332] Preparation of Peptide Having SEQ ID NO. 74 [SEQ. ID. NO. 74] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser-NH ₂

[0333] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M) calculated:3593.0

EXAMPLE 68

[0334] Preparation of Peptide Having SEQ ID NO. 75 [SEQ. ID. NO. 75] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser-NH ₂

[0335] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3535.9

EXAMPLE 69

[0336] Preparation of Peptide Having SEQ ID NO. 76 [SEQ. ID. NO. 76] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro-NH ₂

EXAMPLE 70

[0337] Preparation of Peptide Having SEQ ID NO. 77 [SEQ. ID. NO. 77] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro-NH ₂

[0338] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3448.8

EXAMPLE 71

[0339] Preparation of Peptide Having SEQ ID NO. 78 [SEQ. ID. NO. 78] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly-NH ₂

[0340] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3351.7.

EXAMPLE 72

[0341] Preparation of Peptide Having SEQ ID NO. 79 [SEQ. ID. NO. 79] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly-NH ₂

[0342] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3351.8.

EXAMPLE 73

[0343] Preparation of Peptide Having SEQ ID NO. 80 [SEQ. ID. NO. 80] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Glu Phe Leu Lys Asn Gly-NH ₂

[0344] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Aralytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then, carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3294.7.

EXAMPLE 74

[0345] Preparation of Peptide Having SEQ ID NO. 81 [SEQ. ID. NO. 81] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly tPro Ser Ser Gly Ala tProtPro tPro-NH ₂

[0346] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 37,36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4197.1.

EXAMPLE 75

[0347] Preparation of Peptide Having SEQ ID NO. 82 [SEQ. ID. NO. 82] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala tProtPro tPro-NH ₂

[0348] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 37, 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4179.1.

EXAMPLE 76

[0349] Preparation of Peptide Having SEQ ID NO. 83 [SEQ. ID. NO. 83] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly NMeala Ser Ser Gly Ala ProPro-NH ₂

[0350] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3948.3.

EXAMPLE 77

[0351] Preparation of Peptide Having SEQ ID NO. 84 [SEQ. ID. NO. 84] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Tie Glu Trp Leu Lys Asn Gly Gly NNeala Ser Ser Gly AlaNMeala Nmeala-NH ₂

[0352] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent 2 (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3840.1.

EXAMPLE 78

[0353] Preparation of Peptide Having SEQ ID NO. 85 [SEQ. ID. NO. 85] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro Ser Ser Gly Ala hProhPro-NH ₂

[0354] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4050.1.

EXAMPLE 79

[0355] Preparation of Peptide Having SEQ ID NO. 86 [SEQ. ID. NO. 86] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro Ser Ser Gly Ala hPro-NH ₂

[0356] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. A double coupling is requiredat residue 31. Used in analysis are Solvent A (0.1% TFA in water) andSolvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30% to 60%Solvent B in Solvent A over 30 minutes) of the lyophilized peptide isthen carried out to determine the retention time of the product peptide.Electrospray Mass Spectrometry (M): calculated 3937.1.

EXAMPLE 80

[0357] Preparation of Peptide Having SEQ ID NO. 87 [SEQ. ID. NO. 87] ArgGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH ₂

[0358] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3827.2.

EXAMPLE 81

[0359] Preparation of Peptide Having SEQ ID NO. 88 [SEQ. ID. NO. 88] HisGly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH ₂

[0360] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3394.8.

EXAMPLE 82

[0361] Preparation of Peptide Having SEQ ID NO. 89 [SEQ. ID. NO. 89] HisGly Glu Gly Thr Naphthylala Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu GluAla Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0362] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3289.5.

EXAMPLE 83

[0363] Preparation of Peptide Having SEQ ID NO. 90 [SEQ. ID. NO. 90] HisGly Glu Gly Thr Phe Ser Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Iie Glu Trp Leu Lys Asn-NH ₂

[0364] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN) Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3280.7.

EXAMPLE 84

[0365] Preparation of Peptide Having SEQ ID NO. 91 [SEQ. ID. NO. 91] HisGly Glu Gly Thr Phe Ser Thr Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0366] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3294.7.

EXAMPLE 85

[0367] Preparation of Peptide Having SEQ ID NO. 92 [SEQ. ID. NO. 92] HisGly Glu Gly Thr Phe Thr Ser Glu Leu Ser Lys Gln Met Ala Glu Glu Ala ValArg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0368] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 3 0% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3250.7.

EXAMPLE 86

[0369] Preparation of Peptide Having SEQ ID NO. 93 [SEQ. ID. NO. 93] HisGly Glu Gly Thr Phe Thr Ser Asp pentyigly Ser Lys Gln Leu Glu Glu GluAla Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0370] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide, norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3253.5.

EXAMPLE 87

[0371] Preparation of Peptide Having SEQ ID NO. 94 [SEQ. ID. NO. 94] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Naphthylala Ile Glu Phe Leu Lys Asn-NH ₂

[0372] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3289.5.

EXAMPLE 88

[0373] Preparation of Peptide Having SEQ ID NO. 95 [SEQ. ID. NO. 95] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala ValArg Leu Phe tButylgly Glu Trp Leu Lys Asn-NH ₂

[0374] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3183.4.

EXAMPLE 89

[0375] Preparation of Peptide Having SEQ ID NO. 96 [SEQ. ID. NO. 96] HisGly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ValArg Leu Phe Ile Asp Phe LeU Lys Asn-NH ₂

[0376] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3237.6.

EXAMPLE 90

[0377] Preparation of Peptide Having SEQ ID NO. 97 [SEQ. ID. NO. 97] HisGly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Leu Glu Glu Glu Ala VaiArg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser-NH ₂

[0378] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3637.9.

EXAMPLE 91

[0379] Preparation of Peptide Having SEQ ID NO. 98 His Gly Glu Gly ThrPhe Thr Ser Asp Ala Ser Lys Gln Met Glu [SEQ. ID. NO. 98] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly-NH₂

[0380] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3309.7.

EXAMPLE 92

[0381] Preparation of Peptide Having SEQ ID NO. 99 His Gly Glu Gly ThrPhe Thr Ser Asp Ala Ser Lys Gln Met Glu [SEQ. ID. NO. 99] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro Ser Ser Gly AlahPro hPro-NH₂

[0382] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g), using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 37. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3711.1.

EXAMPLE 93

[0383] Preparation of C-Terminal Carboxylic Acid Peptides Correspondingto the Above C-Terminal Amide Sequences for SEQ ID NOS. 7, 40-61, 68-75,78-80 and 87-96

[0384] Peptides having the sequences of SEQ ID NOS. 7,: 40-61, 68-75,78-80 and 87-96 are assembled on the so called Wang resin(p-alkoxybenzylalcohol resin (Bachem, 0.54 mmole/g)) usingFmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from theresin, deprotected and purified in a similar way to Example 32. Used inanalysis are Solvent A (.0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry provides an experimentally determined (M).

EXAMPLE 94

[0385] Preparation of C-Terminal Carboxylic Acid Peptides Correspondingto the Above C-Terminal Amide Sequences for SEQ ID NOS. 62-67, 76, 77and 81-86

[0386] Peptides having the sequences of SEQ ID NOS. 62-67, 76, 77 and81-86 are assembled on the 2-chlorotritylchloride resin (200-400 mesh),2% DVB (Novabiochem, 0.4-1.0 mmole/g)) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry provides anexperimentally determined (M).

EXAMPLE 95

[0387] Preparation of Peptide Having SEQ ID NO. 100 Ala Gly Glu Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 100] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

[0388] The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.). In general, single-coupling cycles were usedthroughout the synthesis and Fast Moc (HBTU activation) chemistry wasemployed. Deprotection (Fmoc group removal) of the growing peptide chainwas achieved using piperidine. Final deprotection of the completedpeptide resin was achieved using a mixture of triethylsilane (0.2 mL),ethanedithiol (0.2 mL), anisole (0.2 mL), water (0.2 mL,) andtrifluoroacetic acid (15 mL) according to standard methods (Introductionto Cleavage Techniques, Applied Biosystems, Inc.) The peptide wasprecipitated in ether/water (50 mL) and centrifuged. The precipitate wasreconstituted in glacial acetic acid and lyophilized. The lyophilizedpeptide was dissolved in water). Crude purity was about 75%.

[0389] Used in purification steps and analysis were Solvent A (0.1% TFAin water) and Solvent B (0.1% TFA in ACN).

[0390] The solution containing peptide was applied to a preparative C-18column and purified (10% to 40% Solvent B in Solvent A over 40 minutes).Purity of fractions was determined isocratically using a C-18 analyticalcolumn. Pure fractions were pooled furnishing the above-identifiedpeptide. Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide gave product peptide havingan observed retention time of 19.2 minutes. Electrospray MassSpectrometry (M): calculated 3171.6; found 3172.

EXAMPLE 96

[0391] Preparation of Peptide Having SEQ ID NO. 101 His Gly Ala Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO.' 101] Glu Glu AlaVal Arg Leu Phe Tie Giu Phe Leu Lys Asn-NH₂

[0392] The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.9 minutes. Electrospray Mass Spectrometry (M): calculated3179.6; found 3180.

EXAMPLE 97

[0393] Preparation of Peptide Having SEQ ID NO. 102 His Gly Glu Ala ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 102] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

[0394] The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 12.2 minutes. Electrospray Mass Spectrometry (M): calculated3251.6; found 3253.3.

EXAMPLE 98

[0395] Preparation of Peptide Having SEQ ID NO. 103 His Gly Glu Gly ThrPhe Thr Ser Ala Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 103] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

[0396] The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 16.3 minutes. Electrospray Mass Spectrometry (M): calculated3193.6; found 3197.

EXAMPLE 99

[0397] Preparation of Peptide Having SEQ ID NO. 104 Ala Gly Glu Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 104] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

[0398] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3228.6.

EXAMPLE 100

[0399] Preparation of Peptide Having SEQ ID NO. 105 His Gly Ala Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 105] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

[0400] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3234.7.

EXAMPLE 101

[0401] Preparation or Peptide Having SEQ ID NO. 106 His Gly Glu Ala ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 106] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

[0402] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3308.7.

EXAMPLE 102

[0403] Preparation of Peptide Having SEQ ID NO. 107 His Gly Glu Gly ThrPhe Thr Ser Ala Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 107] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

[0404] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3250.7.

EXAMPLE 103

[0405] Preparation of Peptide Having SEQ ID NO. 108 [SEQ. ID. NO. 108]His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0406] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3252.6.

EXAMPLE 104

[0407] Preparation of Peptide Having SEQ ID NO. 109 [SEQ. ID. NO. 109]Ala Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0408] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3200.6.

EXAMPLE 105

[0409] Preparation of Peptide Having SEQ ID NO. 110 [SEQ. ID. NO. 110]Ala Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0410] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3143.5.

EXAMPLE 106

[0411] Preparation of Peptide Having SEQ ID NO. 111 [SEQ. ID. NO. 111]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0412] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55; mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3214.6.

EXAMPLE 107

[0413] Preparation of Peptide Having SEQ ID NO. 112 [SEQ. ID. NO. 112]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0414] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3157.5.

EXAMPLE 108

[0415] Preparation of Peptide Having SEQ ID NO. 113 [SEQ. ID. NO. 113]Ala Gly Asp Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0416] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3184.6.

EXAMPLE 109

[0417] Preparation of Peptide Having SEQ ID NO. 114 [SEQ. ID. NO. 114]Ala Glu Asp Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0418] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product, peptide. Electrospray Mass Spectrometry (M): calculated3127.5.

EXAMPLE 110

[0419] Preparation of Peptide Having SEQ ID NO. 115 [SEQ. ID. NO. 115]Ala Gly Asp Gly Thr NaphthylAla Thr Ser Asp Leu Ser Lys Gln Met Glu GluGlu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0420] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the, resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3266.4.

EXAMPLE 111

[0421] Preparation of Peptide Having SEQ ID NO. 116 [SEQ. ID. NO. 116]Ala Gly Asp Gly Thr Naphthylala Thr Ser Asp Leu Ser Lys Gln Leu Glu GluGlu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0422] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3209.4.

EXAMPLE 112

[0423] Preparation of Peptide Having SEQ ID NO. 117 [SEQ. ID. NO. 117]Ala Gly Asp Gly Thr Phe Ser Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0424] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3200.6.

EXAMPLE 113

[0425] Preparation of Peptide Having SEQ ID NO. 118 Ala Gly Asp Gly ThrPhe Ser Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 118] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

[0426] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3143.5.

EXAMPLE 114

[0427] Preparation of Peptide Having SEQ ID NO. 119 Ala Gly Asp Gly ThrPhe Thr Ala Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 119] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

[0428] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3198.6.

EXAMPLE 115

[0429] Preparation of Peptide Having SEQ ID NO. 120 Ala Gly Asp Gly ThrPhe Thr Ala Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 120] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

[0430] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3141.5.

EXAMPLE 116

[0431] Preparation of Peptide Having SEQ ID NO. 121 Ala Gly Asp Gly ThrPhe Thr Ser Ala Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 1211] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

[0432] The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3170.6.

EXAMPLE 117

[0433] Preparation of Peptide Having SEQ ID NO. 122 Ala Gly Asp Gly ThrPhe Thr Ser Ala Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 122] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

[0434] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3113.5.

EXAMPLE 118

[0435] Preparation of Peptide Having SEQ ID NO. 123 Ala Gly Asp Gly ThrPhe Thr Ser Glu Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 123] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

[0436] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids:(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3228.6.

EXAMPLE 119

[0437] Preparation of Peptide Having SEQ ID NO. 124 Ala Gly Asp Gly ThrPhe Thr Ser Glu Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 124] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

[0438] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3171.6.

EXAMPLE 120

[0439] Preparation of Peptide Having SEQ ID NO. 125 Ala Gly Asp Gly ThrPhe Thr Ser Asp Ala Ser Lys Gln Met Glu [SEQ. ID. NO. 125] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

[0440] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3172.5.

EXAMPLE 121

[0441] Preparation of Peptide Having SEQ ID NO. 126 Ala Gly Asp Gly ThrPhe Thr Ser Asp Ala Ser Lys Gln Leu Glu [SEQ. ID. NO. 126] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

[0442] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3115.4.

EXAMPLE 122

[0443] Preparation of Peptide Having SEQ ID NO. 127 Ala Gly Asp Gly ThrPhe Thr Ser Asp Pentylgly Ser Lys Gln [SEQ. ID. NO. 127] Met Glu Glu GluAla Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

[0444] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3230.4.

EXAMPLE 123

[0445] Preparation of Peptide Having SEQ ID NO. 128 [SEQ. ID. NO. 128]Ala Gly Asp Gly Thr Phe Thr Ser Asp Pertylgly Ser Lys Gln Leu Glu GluGlu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0446] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3198.6.

EXAMPLE 124

[0447] Preparation of Peptide Having SEQ ID NO. 129 [SEQ. ID. NO. 129]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ala Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0448] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3141.5.

EXAMPLE 125

[0449] Preparation of Peptide Having SEQ ID NO. 130 [SEQ. ID. NO. 130]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ala Lys Gln Leu Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0450] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3157.5.

EXAMPLE 126

[0451] Preparation of Peptide Having SEQ ID NO. 131 [SEQ. ID. NO. 131]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0452] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3100.4.

EXAMPLE 127

[0453] Preparation of Peptide Having SEQ ID NO. 132 [SEQ. ID. NO. 132]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln Leu Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0454] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3157.6.

EXAMPLE 128

[0455] Preparation of Peptide Having SEQ ID NO. 133 [SEQ. ID. NO. 133]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0456] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3100.5.

EXAMPLE 129

[0457] Preparation of Peptide Having SEQ ID NO. 134 [SEQ. ID. NO. 134]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala Leu Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0458] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3100.5.

EXAMPLE 130

[0459] Preparation of Peptide Having SEQ ID NO. 135 [SEQ. ID. NO. 135]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Ala Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0460] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3154.5.

EXAMPLE 131

[0461] Preparation of Peptide Having SEQ ID NO. 136 [SEQ. ID. NO. 136]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Ala Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0462] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3115.5.

EXAMPLE 132

[0463] Preparation of Peptide Having SEQ ID NO. 137 [SEQ. ID. NO. 137]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Pentylgly Glu GluGlu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0464] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids.(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3212.4.

EXAMPLE 133

[0465] Preparation of Peptide Having SEQ ID NO. 138 [SEQ. ID NO. 138]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Pentylgly Glu GluGlu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0466] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3173.4.

EXAMPLE 134

[0467] Preparation of Peptide Having SEQ ID NO. 139 [SEQ. ID. NO. 139]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Ala Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0468] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3156.6.

EXAMPLE 135

[0469] Preparation of Peptide Having SEQ ID NO. 140 [SEQ. ID. NO. 140]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Ala Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0470] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3099.5.

EXAMPLE 136

[0471] Preparation of Peptide Having SEQ ID NO. 141 [SEQ. ID. NO. 141]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Ala Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0472] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3156.6.

EXAMPLE 137

[0473] Preparation of Peptide Having SEQ ID NO. 142 [SEQ. ID. NO. 142]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Ala Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0474] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3099.5.

EXAMPLE 138

[0475] Preparation of Peptide Having SEQ ID NO. 143 [SEQ. ID. NO. 143]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Ala AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0476] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3156.6.

EXAMPLE 139

[0477] Preparation of Peptide Having SEQ ID NO. 144 [SEQ. ID. NO. 144]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Ala AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0478] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3099.5.

EXAMPLE 140

[0479] Preparation of Peptide Having SEQ ID NO. 145 [SEQ. ID. NO. 145]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaAla Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0480] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent SA over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3186.6.

EXAMPLE 141

[0481] Preparation of Peptide Having SEQ ID NO. 146 [SEQ. ID. NO. 146]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu AlaAla Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0482] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3129.5.

EXAMPLE 142

[0483] Preparation of Peptide Having SEQ ID NO. 147 [SEQ. ID. NO. 147]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Ala Leu Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0484] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes). of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3129.5.

EXAMPLE 143

[0485] Preparation of Peptide Having SEQ ID NO. 148 [SEQ. ID. NO. 148]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu AlaVal Ala Leu Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0486] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3072.4.

EXAMPLE 144

[0487] Preparation of Peptide Having SEQ ID NO. 149 [SEQ. ID. NO. 149]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Ala Phe Ile Glu Trp Leu Lys Asn-NH ₂

[0488] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3172.5.

EXAMPLE 145

[0489] Preparation of Peptide Having SEQ ID NO. 150 [SEQ. ID. NO. 150]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu AlaVal Arg Ala Phe Ile Glu Phe Leu Lys Asn-NH ₂

[0490] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3115.5.

EXAMPLE 146

[0491] Preparation of Peptide Having SEQ ID NO. 151 [SEQ. ID. NO. 151]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Naphthylala Ile Glu Trp Leu Lys Asn-NH ₂

[0492] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3266.4.

EXAMPLE 147

[0493] Preparation of Peptide Having SEQ ID NO. 152 [SEQ ID. NO. 152]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu GLu AlaVal Arg Leu Naphthylala Ile Glu Phe Leu Lys Asn-NH ₂

[0494] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3209.4.

EXAMPLE 148

[0495] Preparation of Peptide Having SEQ ID NO. 153 [SEQ. ID. NO. 153]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Val Glu Trp Leu Lys Asn-NH ₂

[0496] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3200.6.

EXAMPLE 149

[0497] Preparation of Peptide Having SEQ ID NO. 154 [SEQ. ID. NO. 154]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu AlaVal Arg Leu Phe Val Glu Phe Leu Lys Asn-NH ₂

[0498] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3143.5.

EXAMPLE 150

[0499] Preparation of Peptide Having SEQ ID NO. 155 [SEQ. ID. NO. 155]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe tButylgly Glu Trp Leu Lys Asn-NH ₂

[0500] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3216.5.

EXAMPLE 151

[0501] Preparation of Peptide Having SEQ ID NO. 156 [SEQ. ID. NO. 156]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu AlaVal Arg Leu Phe tButylgly Glu Phe Leu Lys Asn-NH ₂

[0502] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3159.4.

EXAMPLE 152

[0503] Preparation of Peptide Having SEQ ID NO. 157 [SEQ. ID. NO. 157]Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Asp Trp Leu Lys Asn-NH ₂

[0504] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3200.6

EXAMPLE 153

[0505] Preparation of Peptide Having SEQ ID NO. 158 Ala Gly Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 158] Glu Glu AlaVal Arg Leu Phe Ile Asp Phe Leu Lys Asn-NH₂

[0506] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3143.5.

EXAMPLE 154

[0507] Preparation of Peptide Having SEQ ID NO. 159 Ala Gly Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 159] Glu Glu AlaVal Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH₂

[0508] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3099.5.

EXAMPLE 155

[0509] Preparation of Peptide Having SEQ ID NO. 160 Ala Gly Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 160] Glu Glu AlaVal Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH₂

[0510] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3081.4.

EXAMPLE 156

[0511] Preparation of Peptide Having SEQ ID NO. 161 Ala Gly Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 161] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Ala Lys Asn-NH₂

[0512] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3172.5.

EXAMPLE 157

[0513] Preparation of Peptide Having SEQ ID NO. 162 Ala Gly Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 162] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Ala Lys Asn-NH₂

[0514] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3115.5.

EXAMPLE 158

[0515] Preparation of Peptide Having SEQ ID NO. 163 Ala Gly Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 163] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Ala Asn-NH₂

[0516] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3157.5.

EXAMPLE 159

[0517] Preparation of Peptide Having SEQ ID NO. 164 Ala Gly Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 164] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Ala Asn-NH₂

[0518] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray mass Spectrometry (M): calculated3100.4.

EXAMPLE 160

[0519] Preparation of Peptide Having SEQ ID NO. 165 Ala Gly Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 165] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Ala-NH₂

[0520] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3171.6.

EXAMPLE 161

[0521] Preparation of Peptide Having SEQ ID NO. 166 Ala Gly Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 166] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Ala-NH₂

[0522] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3114.5.

EXAMPLE 162

[0523] Preparation of Peptide Having SEQ ID NO. 167 Ala Gly Glu Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 167] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala ProPro Pro-NH₂

[0524] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4033.5.

EXAMPLE 163

[0525] Preparation of Peptide Having SEQ ID NO. 168 His Gly Ala Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 168] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala ProPro Pro-NH₂

[0526] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3984.4.

EXAMPLE 164

[0527] Preparation of Peptide Having SEQ ID NO. 169 His Gly Glu Ala ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 169] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala ProPro-NH₂

[0528] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4016.5.

EXAMPLE 165

[0529] Preparation of Peptide Having SEQ ID NO. 170 His Gly Glu Gly ThrPhe Thr Ser Ala Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 170] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser GJy AlaPro-NH₂

[0530] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3861.3.

EXAMPLE 166

[0531] Preparation of Peptide Having SEQ ID NO. 171 Ala Gly Glu Gly ThrPhe Thr Ser Asp Ala Ser Lys Gln Leu Glu [SEQ. ID. NO. 171] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly AlaPro-NH₂

[0532] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3746.1.

EXAMPLE 167

[0533] Preparation of Peptide Having SEQ ID NO. 172 Ala Gly Glu Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 172] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH₂

[0534] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3742.1.

EXAMPLE 168

[0535] Preparation of Peptide Having SEQ ID NO. 173 His Gly Ala Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 173] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH₂

[0536] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3693.1.

EXAMPLE 169

[0537] Preparation of Peptide Having SEQ ID NO. 174 His Gly Glu Ala ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ ID. NO. 174] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly-NH₂

[0538] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3751.2.

EXAMPLE 170

[0539] Preparation of Peptide Having SEQ ID NO. 175 His Gly Glu Gly ThrPhe Thr Ser Ala Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 175] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser-NH₂

[0540] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3634.1.

EXAMPLE 171

[0541] Preparation of Peptide Having SEQ ID NO. 176 Ala Gly Glu Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu [SEQ. ID. NO. 176] Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser-NH₂

[0542] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3526.9.

EXAMPLE 172

[0543] Preparation of Peptide Having SEQ ID NO. 177 His Gly Ala Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 177] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser-NH₂

[0544] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3477.9.

EXAMPLE 173

[0545] Preparation of Peptide Having SEQ ID NO. 178 [SEQ. ID. NO. 178]His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro-NH ₂

[0546] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3519.9.

EXAMPLE 174

[0547] Preparation of Peptide Having SEQ ID NO. 179 [SEQ. ID. NO. 179]His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Leu Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly-NH ₂

[0548] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3307.7.

EXAMPLE 175

[0549] Preparation of Peptide Having SEQ ID NO. 180 [SEQ. ID. NO. 180]Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly-NH ₂

[0550] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3186.5.

EXAMPLE 176

[0551] Preparation of Peptide Having SEQ ID NO. 181 [SEQ. ID. NO. 181]His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly tPro Ser Ser Gly AlatPro tPro tPro-NH ₂

[0552] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Double couplings are requiredat residues 37, 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4121.1.

EXAMPLE 177

[0553] Preparation of Peptide Having SEQ ID NO. 182 [SEQ. ID. NO. 182]His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala tProtPro tPro-NH ₂

[0554] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Double-couplings are requiredat residues 37, 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4173.2.

EXAMPLE 178

[0555] Preparation of Peptide Having SEQ ID NO. 183 [SEQ. ID. NO. 183]His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly NMeala Ser Ser Gly AlaNMeala NMeala-NH ₂

[0556] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN) . Analytical RP-HPLC (gradient30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3796.1.

EXAMPLE 179

[0557] Preparation of Peptide Having SEQ ID NO. 184 [SEQ. ID. NO. 184]Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro Ser Ser Gly AlahPro- NH ₂

[0558] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. A double coupling is requiredat residue 31. Used in analysis are Solvent A (0.1% TFA in water) andSolvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30% to 60%Solvent B in Solvent A over 30 minutes) of the lyophilized peptide isthen carried out to determine the retention time of the product peptide.Electrospray Mass Spectrometry (M): calculated 3871.1.

EXAMPLE 180

[0559] Preparation of Peptide Having SEQ ID NO. 185 [SEQ. ID. NO. 185]His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH ₂

[0560] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3750.2.

EXAMPLE 181

[0561] Preparation of Peptide Having SEQ ID NO. 186 [SEQ. ID. NO. 186]His Gly Asp Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH ₂

[0562] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3408.8.

EXAMPLE 182

[0563] Preparation of Peptide Having SEQ ID NO. 187 [SEQ. ID. NO. 187]Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala ProPro Pro Ser-NH ₂

[0564] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4120.6.

EXAMPLE 183

[0565] Preparation of Peptide Having SEQ ID NO. 188 Ala Gly Ala Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Leu Glu [SEQ. ID. NO. 188] Glu Glu AlaVal Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala ProPro Pro Ser-NH₂

[0566] The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4005.5.

EXAMPLE 184

[0567] Preparation of C-Terminal Carboxylic Acid Peptides Correspondingto the Above C-Terminal Amide Sequences for Peptides Having SEQ ID NOS.100-166, 172-177, 179-180 and 185-188

[0568] C-terminal carboxylic acid peptides corresponding to amidatedhaving SEQ ID NOS. 100-166, 172-177, 179-180 and 185-188 are assembledon the so called Wang resin (p-alkoxybenzylalcohol resin (Bachem, 0.54mmole/g)) using Fmoc-protected amino acids (Applied Biosystems, Inc.),cleaved from the resin, deprotected and purified in a similar way tothat described in Example 95. Used in analysis are Solvent A (0.1% TFAin water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient30% to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry provides anexperimentally determined (M).

EXAMPLE 185

[0569] Preparation of C-Terminal Carboxylic Acid Peptides Correspondingto the Above C-Terminal Amide Sequences for Peptides Having SEQ ID NOS.167-171, 178 and 181-184

[0570] C-terminal carboxylic acid peptides corresponding to amidated SEQID NOS. 167-171, 178 and 181-184 are assembled on the2-chlorotritylchloride resin (200-400 mesh), 2% DVB (Novabiochem,0.4-1.0 mmole/g)) using Fmoc-protected amino acids (Applied Biosystems,Inc.), cleaved from the resin, deprotected and purified in a similar wayto that described in Example 95. Used in analysis are Solvent A (0.1%TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry provides anexperimentally determined (M).

EXAMPLE 186

[0571] Evaluation of Ability to Cross Placenta

[0572] I. Introduction

[0573] The purpose of this experiment was to determine whether thisexendin-4, when delivered to the maternal circulation, is transportedacross the placenta and is detectable in amniotic fluid or fetal blood.

[0574] II. Materials and Methods

[0575] Animals:

[0576] Female Harlan Sprague Dawley rats (age 12 weeks, 17-21 dayspregnant, approximately 300 grams) were housed at 22.8±0.8° C. in a12:12 hour light dark cycle. All experiments were performed during thelight cycle. Animals were given free access to food and water until thestart of the experiment.

[0577] Sample Collection:

[0578] Rats were anesthetized with 5% halothane and then maintained with2% halothane during the surgical procedures.

[0579] Body temperature was measured and controlled using a thermistorprobe/controller (Model 73A, YSI, Yellow Springs, Ohio) and a heatedoperating table. Blood was collected from the tail vein immediatelyprior to a subcutaneous injection of exendin-4 (AC2993 AmylinPharmaceuticals, Inc.) or vehicle (100μl 0.15M NaCl) at t=0. At t=30minutes, when plasma concentrations following a subcutaneous injectionhave been found to be maximal, another blood sample was taken.Immediately thereafter, a midline laparotomy was made to expose theuterine horns. Fluid was collected from the individual amniotic sacs byaspiration through a 16 g needle into a syringe. The amniotic fluidsfrom individual fetuses were pooled from a given rat, but fluids fromeach rat were kept separate. Fetal blood was collected by heart puncturewith a 28 g microfine needle and aspirated into a syringe. Amnioticfluid and fetal blood samples were collected within 10 minutes of whenthe laparotomy was made. (t=30-40 min.). All blood and fluid sampleswere centrifuged. The plasma or supernatant was stored at −70° C. untilassayed.

[0580] Treatment Groups:

[0581] There were 2 treatment groups:

[0582] Group A: Rats receiving exendin-4 dissolved at 21 μg/100 μl in0.15M NaCl n=4.

[0583] Group B: Rats receiving exendin-4 dissolved at 21 μg/100 μl in0.15M NaCl n=5.

[0584] III. Results

[0585] Exendin-4 was not detected in any of the baseline samples, takenat t=0, when measured by a specific IRMA (immuno-radio-metric-assay)which has a LLQ (low limit of quantitation) of 15 pM. At t=30 plasmalevels of exendin-4 in the mother rats that received 21 μg exendin-4were 16.47 nM±2.45. Values obtained from amniotic fluid (6.1±5.3 pM) andfetal blood (12.7±6.5 pM) were 2700-fold and 1300-fold less than thosein plasma and were generally below the lower limit of quantitation ofthe assay (FIG. 2). Similar results were obtained with the ratsreceiving 210 μg exendin-4 where plasma levels in the mother rats att=30 were 232.16 nM±63.45 (FIG. 3). Values obtained from amniotic fluid(18.3±9.3 pM) and fetal blood (16.9±13.8 pM) were 12,680-fold and13,750-fold less than those in plasma and were undetectable in over halfof the samples.

[0586] IV. Discussion

[0587] The placenta is the organ responsible for nutrient and wasteexchange between the fetus and the mother. Maternal and fetalcirculations are separated by an epithelial layer that allows or deniesdiffusion or carrier mediated transport of substances across theinterface. The risk of adverse effects on the fetus can be related tothe extent to which the drug enters the fetal circulation. The dataobtained here indicate that, even with high injected doses, which mayexceed the per-kilogram doses administered to humans by up to 3000-fold,little or no exendin-4 appeared in the fetal circulation or amnioticfluid. Six out of 15 measurements were above the lower limit ofquantitation, and in 9 of 15, exendin-4 was undetectable. In thosesamples in which exendin-4 was measurable, its presence may have beendue to contamination from maternal blood (which need be present only at1:1,000-1:10,000 to be measurable). Such contamination is possiblefollowing laparotomy of the dam and puncture of the fetus.

[0588] Various modifications of the invention in addition to those shownand described herein will become apparent to those skilled in the artfrom the foregoing description and fall within the scope of thefollowing claims.

We claim:
 1. A method for treating gestational diabetes mellitus in asubject comprising administering to said subject a therapeuticallyeffective amount of an exendin or an exendin agonist.
 2. The methodaccording to claim 1 wherein said exendin or exendin agonist isadministered continuously.
 3. The method according to claim 1 whereinsaid administration is by injection.
 4. The method according to claim 3wherein the injection is a subcutaneous injection.
 5. The methodaccording to claim 1 wherein about 1 μg-30 μg to about 1 mg of theexendin or exendin agonist is administered per day.
 6. The methodaccording to claim 1 wherein about 1 μg-30 μg to about 500 μg of theexendin or exendin agonist is administered per day.
 7. The methodaccording to claim 1 wherein about 1 μg-30 μg to about 100 μg of theexendin or exendin agonist is administered per day.
 8. The methodaccording to claim 1, wherein about 3 μg to about 50 μg of the exendinor exendin agonist is administered per day.
 9. The method of claim 1wherein said subject is human.
 10. A method for reducing blood glucoselevel of a subject having gestational diabetes mellitus comprisingadministering to said subject a therapeutically effective amount of anexendin or an exendin agonist.
 11. The method according to any of claims1-10 wherein said exendin is exendin-3.
 12. The method according to anyof claims 1-10 wherein said exendin is exendin-4.
 13. The methodaccording to any of claims 1-10 wherein said exendin agonist is selectedfrom the group consisting of exendin-4 acid, exendin-4 (1-30), exendin-4(1-30) amide, exendin-4 (1-28) amide, ¹⁴Leu, ²⁵Phe exendin-4 amide, and¹⁴Leu, ²⁵Phe exendin-4 (1-28) amide.
 14. The method according to any ofclaims 1-10 further comprising administering a therapeutically effectiveamount of one or more compounds selected from the group consisting of aninsulin and an amylin agonist.
 15. The method according to any of claims1-10 wherein said exendin agonist is an exendin agonist according toFormula I.
 16. The method according to any of claims 1-10 wherein saidexendin agonist is an exendin agonist according to Formula II.
 17. Themethod according to any of claims 1-10 wherein said exendin agonist isan exendin agonist according to Formula III.